JP2005539022A - Composition of cyclooxygenase-2 selective inhibitor and carbonic anhydrase inhibitor for the treatment of malignant tumors - Google Patents

Abstract

The present invention provides compositions and methods for the treatment of malignant tumors in patients. More specifically, the present invention provides a combination therapy for the treatment of malignancy comprising the administration to a patient of a carbonic anhydrase inhibitor in combination with a cyclooxygenase-2 selective inhibitor.

Description

  The present invention provides compositions and methods for the treatment of malignant tumors. More particularly, the present invention is directed to a combination therapy for the treatment or prevention of malignancy comprising the administration to a patient in combination of a carbonic anhydrase inhibitor with a cyclooxygenase-2 inhibitor. .

  At present, the management of non-surgical cancer treatment is one or more highly toxic chemotherapeutic agents after the cancer has progressed to a point where the therapeutic benefit of chemotherapy / hormones exceeds its dangerous side effects. Or administering a hormone therapy agent to the patient. As a result of these side effects, standard chemotherapeutic agents are typically used only for short periods of time with frequent therapy changes and treatment pauses so that patients are not overwhelmed by drug side effects. Thus, at a certain risk-benefit condition, side effects are routinely associated with initiating chemotherapy when patients show precancerous lesions or preventing their recurrence after the cancer has been removed. Continuing chemotherapy or hormonal therapy is typically ruled out.

Cancer and precancer studies have been filled with publications that describe various biological molecules that are overexpressed in malignant tumor tissues, and some groups have identified whether specific overexpressed molecules are responsible for the disease. And if such overexpression is inhibited, it has led to studies on whether malignant tumors can be alleviated. One such biological molecule that has been extensively studied as a therapeutic target for the treatment of malignant tumors is prostaglandin, a naturally occurring C-20 unsaturated fatty acid. As an example, in familial adenomatous polyposis (“FAP”), Waddell et al. Described non-steroidal anti-inflammatory drugs because prostaglandins are overexpressed in such polyps. : "NSAID") hypothesized that NSAIDs alleviate symptoms because they inhibit the synthesis of prostaglandins. Therefore, he administered NSAID sulindac (an inhibitor of PGE ₂ ) to several FAP patients. Found that polyps regressed and did not recur in therapeutic treatment with NSAIDs. PGE ₂ inhibition is the result of inhibition of cyclooxygenase (COX) by NSAIDs.

  Patients treated with NSAIDs typically show far fewer side effects than with conventional chemotherapy or hormones, but the use of very high doses of common NSAIDs is a dangerous side effect including life-threatening ulcers Which limits its therapeutic potential. One reason presented for the dangerous side effects associated with conventional NSAIDs is their non-selective inhibition of both the cyclooxygenase enzyme (COX) commonly known as COX-1 and COX-2. COX-1 is constitutively expressed and mediates many physiological functions such as kidney and gastrointestinal functions. In contrast, COX-2 expression is stimulated by many inflammatory cytokines, growth factors, oncogenes, lipopolysaccharides, and tumor promoters. While conventional NSAIDs block both forms of the enzyme, a new group of NSAIDs, selective cyclooxygenase-2 inhibitors, reduce the inflammation more effectively and produce less and less severe side effects Provides a target for specific inhibition.

  COX-2 stimulates epithelial cell proliferation, inhibits apoptosis, stimulates angiogenesis, improves cell invasiveness, mediates immunosuppression, and increases mutagen production It plays a key role in tumorigenesis. The results of several studies using mouse models of colorectal cancer and the results of clinical trials indicate that COX-2 is a useful target for the prevention and treatment of colorectal cancer (Fernandex et al. (2002) In Vivo 16 (6): 501-509). Studies with several other epithelial cancers, including different organ sites such as breast, prostate, bladder, lung, and pancreas, suggest that COX-2 plays an important role in the pathogenesis of these cancers (See, eg, Singh et al., (2002) J. Surg. Res. 108 (1): 173-179 for its role in breast cancer; Sonoshita et al. For its role in fibroblasts and endothelial cells. al., (2002) Cancer Res. 62 (23): 6846-6849; see Li et al., (2002) 21 (6): 625-629 for its role in gastric cells).

SUMMARY OF THE INVENTION Within several aspects of the present invention, methods and compositions for the treatment of malignant tumors in patients are provided. Said composition comprises a cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof and a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt or prodrug thereof. In another aspect, the method comprises a cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof, a carbonic anhydrase inhibitor or a pharmaceutically acceptable salt or prodrug thereof. And administering to the patient in combination.

  In one embodiment, the cyclooxygenase-2 selective inhibitor is a member of the chromene group of compounds. For example, a chromene compound or a pharmaceutically acceptable salt or prodrug thereof has the following formula:

[Where:
n is an integer that is 0, 1, 2, 3 or 4;
G is O, S or NR ^a ;
R ^a is alkyl;
R ¹ is selected from the group consisting of H and aryl;
R ² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
R ³ is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and each R ⁴ is , H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, Amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, hete Independently from the group consisting of cyclosulfonyl, alkylsulfonyl, hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl Selected;
Or R ⁴ together with the carbon atom to which it is attached and the remainder of ring E form a naphthyl radical;
It can be the compound of.

  In another embodiment, the cyclooxygenase-2 selective inhibitor or pharmaceutically acceptable salt or prodrug thereof has the following formula:

[Where:
A is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclyl ring;
R ₁ is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R ¹ is alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, Optionally substituted at substitutable positions with one or more radicals selected from arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
R ₂ is selected from the group consisting of methyl or amino; and R ₃ is H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cyclo Alkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, Aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocal Nilalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkyl Amino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, Aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, aryl Ruhoniru is selected from the group consisting of radicals chosen from N- alkyl -N- arylaminosulfonyl;]
A compound comprising

  In yet another embodiment, the carbonic anhydrase inhibitor is dorzolamide. In another embodiment, the carbonic anhydrase inhibitor is acetazolamide. In yet another embodiment, the carbonic anhydrase inhibitor is dichlorophenamide. In still further embodiments, the carbonic anhydrase inhibitor is brinzolamide. In another embodiment, the carbonic anhydrase inhibitor is metazolamide.

  Other aspects of the invention are described in further detail below.

The abbreviation and definition term “acyl” is a radical provided by a residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such lower alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl.

  The term “alkenyl” is a straight or branched radical having at least one carbon-carbon double bond of 2 to about 20 carbon atoms, or preferably of 2 to about 12 carbon atoms. More preferably, the alkenyl radical is a “lower alkenyl” radical having 2 to about 6 carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.

  The terms “alkenyl” and “lower alkenyl” are further radicals having “cis” and “trans” configurations, or alternatively, “E” and “Z” configurations. The term “cycloalkyl” is a saturated carbocyclic radical having 3 to 12 carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” having 3 to about 8 carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

  The terms “alkoxy” and “alkyloxy” are straight or branched oxy-containing radicals each having an alkyl portion of 1 to about 10 carbon atoms. More preferred alkoxy radicals are “lower alkoxy” radicals having 1 to 6 carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.

  The term “alkoxyalkyl” is an alkyl radical having one or more alkoxy radicals connected to an alkyl radical, ie, forming monoalkoxyalkyl and dialkoxyalkyl radicals. An “alkoxy” radical can be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to give a haloalkoxy radical. More preferred haloalkoxy radicals are “lower haloalkoxy” radicals having 1 to 6 carbon atoms and one or more halo radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.

  The term “alkoxycarbonyl” means a radical containing an alkoxy radical as defined above connected to a carbonyl radical via an oxygen atom. Further preferred are “lower alkoxycarbonyl” radicals having an alkyl moiety having 1 to 6 carbon atoms. Examples of such lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.

  When used alone or within other terms such as “haloalkyl”, “alkylsulfonyl”, “alkoxyalkyl” and “hydroxyalkyl”, the term “alkyl” refers to 1 to about 20 carbons. A straight chain, cyclic or branched radical having an atom, or preferably 1 to about 12 carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having 1 to about 10 carbon atoms. Most preferred are lower alkyl radicals having 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.

  The term “alkylamino” is an amino group substituted with one or two alkyl radicals. Preferred is a “lower N-alkylamino” radical having an alkyl moiety having 1 to 6 carbon atoms. Suitable lower alkylamino can be mono- or dialkylamino such as N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino and the like.

The term “alkylaminoalkyl” is a radical having one or more alkyl radicals attached to an aminoalkyl radical.
The term “alkylaminocarbonyl” is an aminocarbonyl group substituted on the amino nitrogen atom with one or two alkyl radicals. Preferred are “N-alkylaminocarbonyl” and “N, N-dialkylaminocarbonyl” radicals. Further preferred are “lower N-alkylaminocarbonyl” “lower N, N-dialkylaminocarbonyl” radicals having a lower alkyl moiety as defined above.

  The terms “alkylcarbonyl”, “arylcarbonyl” and “aralkylcarbonyl” include radicals having alkyl, aryl and aralkyl radicals as defined above attached to a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl and benzylcarbonyl.

  The term “alkylthio” is a radical containing a straight or branched alkyl radical of 1 to about 10 carbon atoms connected to a divalent sulfur atom. More preferred alkylthio radicals are “lower alkylthio” radicals having an alkyl radical of 1 to 6 carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio.

  The term “alkylthioalkyl” is a radical containing an alkylthio radical connected to an alkyl radical of 1 to about 10 carbon atoms through a divalent sulfur atom. More preferred alkylthioalkyl radicals are “lower alkylthioalkyl” radicals having an alkyl radical of 1 to 6 carbon atoms. Examples of such lower alkylthioalkyl radicals include methylthiomethyl.

  The term “alkylsulfinyl” is a radical containing a straight or branched alkyl radical of 1 to 10 carbon atoms connected to a divalent —S (═O) — radical. More preferred alkylsulfinyl radicals are “lower alkylsulfinyl” radicals having an alkyl radical of 1 to 6 carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.

  The term “alkynyl” is a straight or branched radical having 2 to about 20 carbon atoms, or preferably 2 to about 12 carbon atoms. More preferred alkynyl radicals are “lower alkynyl” radicals having 2 to about 10 carbon atoms. Most preferred is a lower alkynyl radical having 2 to about 6 carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.

  The term “aminoalkyl” is an alkyl radical substituted with one or more amino radicals. More preferred are “lower aminoalkyl” radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like.

The term “aminocarbonyl” is an amide group of the formula —C (═O) NH 2.
The term “aralkoxy” is an aralkyl radical connected to another radical via an oxygen atom.

The term “aralkoxyalkyl” is an aralkoxy radical connected to an alkyl radical via an oxygen atom.
The term “aralkyl” is an alkyl radical substituted with an aryl such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in the aralkyl can be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable.

  The term “aralkylamino” is an aralkyl radical connected to another radical via the amino nitrogen atom. The terms “N-arylaminoalkyl” and “N-aryl-N-alkyl-aminoalkyl” each represent an amino substituted with one aryl radical or with one aryl and one alkyl radical and connected to an alkyl radical. An amino group having a group. Examples of such radicals include N-phenylaminomethyl and N-phenyl-N-methylaminomethyl.

The term “aralkylthio” is an aralkyl radical connected to a sulfur atom.
The term “aralkylthioalkyl” is an aralkylthio radical connected to an alkyl radical via a sulfur atom.

  The term “aroyl” is an aryl radical having a carbonyl radical as defined above. Examples of aroyl include benzoyl, naphthoyl and the like, and the aryl in said aroyl can be further substituted.

  The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings, wherein such rings are connected together in a pendant fashion. Or can be condensed. The term “aryl” is an aromatic radical such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The aryl moiety is further alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxy It can be substituted at a substitutable position with one or more substituents independently selected from carbonyl and aralkoxycarbonyl.

  The term “arylamino” is an amino group, such as N-phenylamino, which is substituted with one or two aryl radicals. An “arylamino” radical can be further substituted in the aryl ring portion of the radical.

The term “aryloxyalkyl” is a radical having an aryl radical connected to the alkyl group via a divalent oxygen atom.
The term “arylthioalkyl” is a radical having an aryl radical connected to the alkyl radical via a divalent sulfur atom.

As used herein, the term "carbonic anhydrase" is, CO ₂ and _{H 2 CO 3 (CO 2 +} O 2 → HCO 2 - + H +) None of the metalloprotein enzymes that catalyze the interconversion of Refers to an isomer.

The term “carbonyl”, whether used alone or with other terms such as “alkoxycarbonyl”, is — (C═O) —.
The term “carboxy” or “carboxyl”, whether used alone or with other terms such as “carboxyalkyl” is —CO 2 H.

  The term “carboxyalkyl” is an alkyl radical substituted with a carboxy radical. Further preferred are “lower carboxyalkyl” which is a lower alkyl radical as defined above and can be further substituted with halo in the alkyl radical. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl.

  The term “cycloalkenyl” is a partially unsaturated carbocyclic radical having 3 to 12 carbon atoms. More preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having 4 to about 8 carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl.

The term “cyclooxygenase-2 selective inhibitor” is a compound capable of inhibiting cyclooxygenase-2 without significant inhibition of cyclooxygenase-1. Preferably, it has an IC ₅₀ of cyclooxygenase-2 of less than about 0.2 micromolar and a selection of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, and more preferably at least 100 Including compounds having a sex ratio. Even more preferably, the compound has an IC ₅₀ of cyclooxygenase-1 of greater than about 1 micromolar and more preferably greater than 10 micromolar. Inhibitors of the cyclooxygenase pathway of arachidonic acid metabolism used in the methods of the present invention can inhibit enzyme activity by various mechanisms. By way of example and not limitation, inhibitors used in the methods described herein can directly block enzyme activity by acting as a substrate for the enzyme.

The term “halo” means a halogen such as fluorine, chlorine, bromine or iodine.
The term “haloalkyl” is a radical in which any one or more alkyl carbon atoms are replaced with halo as defined above. Specifically included are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. As one example, a monohaloalkyl radical can have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals can have two or more identical halo atoms or combinations of separate halo radicals. A “lower haloalkyl” is a radical having 1-6 carbon atoms. Examples of haloalkyl radicals are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, Includes dichloroethyl and dichloropropyl.

  The term “heteroaryl” is an unsaturated heterocyclyl radical. Examples of unsaturated heterocyclyl radicals, also referred to as “heteroaryl” radicals, are unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, Pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (for example, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (for example, 1H- Unsaturated fused heterocyclyl groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzoimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolo Pyridazinyl (eg Tetrazolo [1,5-b] pyridazinyl, etc.); unsaturated 3-6 membered heteromonocyclic groups containing one oxygen atom, eg pyranyl, furyl, etc .; one sulfur atom Containing unsaturated 3- to 6-membered heteromonocyclic groups such as thienyl, etc .; unsaturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms Cyclic groups such as oxazolyl, isoxazolyl, oxadiazolyl (eg 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) and the like; 1 to 2 oxygen atoms and Unsaturated fused heterocyclyl groups containing 1 to 3 nitrogen atoms (eg benzoxazolyl, benzooxadiazolyl, etc.); 1 to 2 sulfur atoms and 1 to 3 Unsaturated 3- to 6-membered heteromonocyclic groups containing a nitrogen atom, such as thiazolyl, thiadiazolyl (eg 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl) And the like; unsaturated fused heterocyclyl groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (for example, benzothiazolyl, benzothiadiazolyl, etc.) and the like. The term further includes radicals where heterocyclyl radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. The “heterocyclyl group” may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino.

  The term “heterocyclyl” is a cyclic radical containing saturated, partially unsaturated and unsaturated heteroatoms, where the heteroatoms can be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals are saturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (eg pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); 1 to 2 oxygen atoms And saturated 3- to 6-membered heteromonocyclic groups containing 1 to 3 nitrogen atoms (eg morpholinyl, etc.); saturated containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms Includes 3-6 membered heteromonocyclic groups (eg, thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.

  The term “heterocyclylalkyl” refers to alkyl radicals substituted with saturated and partially unsaturated heterocyclyl such as pyrrolidinylmethyl, and heteroaryls such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl. A substituted alkyl radical. The heteroaryl in the heteroaralkyl can be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.

  The term “hydrido” is a single hydrogen atom (H). The hydride radical can be connected, for example, to an oxygen atom to form a hydroxyl radical, or two hydride radicals can be connected to a carbon atom to form a methylene (—CH 2 —) radical.

  The term “hydroxyalkyl” is a straight or branched alkyl radical having 1 to about 10 carbon atoms, any one of which can be substituted with one or more hydroxy radicals. More preferred hydroxyalkyl radicals are “lower hydroxyalkyl” radicals having 1 to 6 carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.

  As used herein, the term “inhibit” refers to the severity of a malignant tumor or malignant neoplastic disease as either a COX-2 selective inhibitor or a carbonic anhydrase inhibitor herein. Means reduced compared to what occurs in the absence of administration of the identified compound.

  As used herein, the term “inhibitor” refers to an enzyme inhibitor, such as an inhibitor of carbonic anhydrase or cyclooxygenase, unless otherwise indicated. Enzyme inhibitors are drugs and / or compounds that stop, prevent, or reduce the rate of enzymatic reactions by any mechanism, including but not limited to competitive inhibition, non-competitive inhibition, and non-competitive inhibition. is there.

  The term “pharmaceutically acceptable” means that the modified noun is suitable for use in a pharmaceutical product; that is, a therapeutic that a “pharmaceutically acceptable” substance is distinguishable by itself. Although not necessarily beneficial, it is used adjective herein to mean relatively safe and / or non-toxic. Pharmaceutically acceptable cations include metal ions and organic ions. Further preferred metal ions include, but are not limited to, suitable alkali metal salts, alkaline earth metal salts and other physiologically acceptable metal ions. Exemplary ions include their normal valence aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic ions include protonated thirds that include, in part, trimethylamine, diethylamine, N, N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Contains amines and quaternary ammonium cations. Exemplary pharmaceutically acceptable acids include, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitrate Including acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid, oxalic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.

  The term “prevention” includes either preventing the development of all clinically apparent malignancies in an at-risk individual or preventing the preclinical manifestation of malignant tumors. . Also encompassed by this definition is the prevention of malignant tumor cell initiation or the inhibition or reversal of progression of pre-malignant tumor cells to malignant cells. This includes prophylactic treatment of those at risk of speaking malignant tumors.

  The term “prodrug” refers to a chemical compound that can be converted into a therapeutic compound by metabolism or a simple chemical process in a patient's body. For example, a group of prodrugs of COX-2 inhibitors are described in US Pat. No. 5,932,598, incorporated herein by reference.

  The term “patient” for therapeutic purposes includes any human or animal patient that is sensitive to adverse effects resulting from a decrease in blood flow to the central nervous system. The patient can be a livestock tumor, a research animal species, a zoo animal species, or a companion animal. In one embodiment, the patient is a mammal. In another embodiment, the mammal is a human.

The term “sulfonyl”, whether used alone or linked to other terms such as alkylsulfonyl, is the divalent radical —SO ₂ —. “Alkylsulfonyl” is an alkyl radical connected to a sulfonyl radical. More preferred alkylsulfonyl radicals are “lower alkylsulfonyl” radicals having 1 to 6 carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. An “alkylsulfonyl” radical can be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to give a haloalkylsulfonyl radical. The terms “sulfamyl”, “aminosulfonyl” and “sulfonamidyl” are NH ₂ O ₂ S—.

  The phrase “therapeutically effective” means the amount of each drug (ie, cyclooxygenase) that achieves the goal of improving the severity of the disease and the frequency of onset for treatment with no drug or with each drug itself. -2) The amount of selective inhibitor and carbonic anhydrase inhibitor) is intended to be limited.

  The term “treatment” includes partial or total inhibition of malignant tumor growth, expansion or metastasis, as well as partial or total destruction of malignant tumor cells. Treatment includes prevention of malignant tumors or related diseases.

DESCRIPTION OF PREFERRED EMBODIMENTS The present invention provides administration to a patient in a combination of a therapeutically effective amount of a COX-2 selective inhibitor and a therapeutically effective amount of a second compound, a carbonic anhydrase inhibitor. A combination therapy comprising: Combination therapy can be used to treat or prevent malignant tumors or diseases associated with malignant tumors. When used as part of a combination therapy, a COX-2 selective inhibitor is administered with a carbonic anhydrase inhibitor, either a carbonic anhydrase inhibitor or a COX-2 selective inhibitor alone. Compared to give improved treatment options.

Cyclooxygenase-2 selective inhibitors Many suitable cyclooxygenase-2 selective inhibitors or pharmaceutically acceptable salts or prodrugs can be used in the compositions of the present invention. In one embodiment, the cyclooxygenase-2 selective inhibitor is, for example, the following formula B-1:

It can be a cyclooxygenase-2 selective inhibitor (CAS Registry Number 71125-38-7), meloxicam, or a pharmaceutically acceptable salt or prodrug.
In yet another embodiment, the cyclooxygenase-2 selective inhibitor has the following formula B-2:

6-[[5- (4-Chlorobenzoyl) -1,4-dimethyl-1H-pyrrol-2-yl] methyl] -3, a cyclooxygenase-2 selective inhibitor of (CAS Registry Number 179382-91-3) (2H) -pyridazinone, or a pharmaceutically acceptable salt or prodrug thereof.

  In yet another embodiment, the cyclooxygenase-2 selective inhibitor is a chromene compound, ie, a substituted benzopyran or a substituted benzopyran analog, and still more typically a substituted benzothiopyran, dihydroquinoline, Selected from the group consisting of dihydronaphthalene or a compound having Formula I shown below, and by way of example and not limitation, has the structure disclosed in Table 1x. In addition, benzopyran cyclooxygenase-2 selective inhibitors useful in the practice of the methods of the present invention are described in US Pat. Nos. 6,034,256 and 6,077, which are all incorporated herein by reference. No. 850.

  In one embodiment, the cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof has the following formula I:

[Wherein n is an integer of 0, 1, 2, 3 or 4;
Where G is O, S or NR ^a ;
Where R ^a is alkyl;
Wherein R ¹ is selected from the group consisting of H and aryl;
Wherein R ² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl, and alkoxycarbonyl;
Wherein R ³ is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and R ⁴ is H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkyl Amino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl , Heterocyclosulfonyl, alkylsulfonyl, hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl Independently selected;
Or R ⁴ together with the carbon atom to which it is attached and the remainder of ring E form a naphthyl radical;
A chromene compound represented by:

Cyclooxygenase-2 selective inhibitors further include:
n is an integer of 0, 1, 2, 3 or 4;
G is O, S or NR ^a ;
R ¹ is H;
R ^a is alkyl;
R ² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
R ³ is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl, wherein haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl are each selected from the group consisting of alkylthio, nitro, and alkylsulfonyl Each independently R ⁴ is optionally substituted with one or more radicals; and each R ⁴ is hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy , Alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylamino Sulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl And independently selected from the group consisting of alkylcarbonyl; or wherein R ⁴ together with ring E forms a naphthyl radical;
It can also be a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.

In a further embodiment, the cyclooxygenase-2 selective inhibitor further comprises:
n is an integer of 0, 1, 2, 3 or 4;
G is oxygen or sulfur;
R ¹ is H;
R ² is carboxyl, lower alkyl, lower aralkyl or lower alkoxycarbonyl;
R ³ is lower haloalkyl, lower cycloalkyl or phenyl; and each R ⁴ is H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, Lower alkylaminosulfonyl, 5 membered heteroarylalkylaminosulfonyl, 6 membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5 membered nitrogen containing heterocyclosulfonyl, 6 membered nitrogen containing heterocyclosulfonyl, lower alkylsulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, or lower alkyl carbonyl; or R ⁴ wherein, This is a naphthyl radical together with the remainder of the carbon atoms and ring E are connected It is formed;
It can also be a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.

Cyclooxygenase-2 selective inhibitors further include:
R ² is carboxyl;
R ³ is lower haloalkyl; and each R ⁴ is H, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkyl Is aminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, or lower alkylcarbonyl; or Where R ⁴ together with ring E forms a naphthyl radical;
It can also be a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.

Cyclooxygenase-2 selective inhibitors further include:
n is an integer of 0, 1, 2, 3 or 4;
R ³ is fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, or trifluoromethyl; and the respective R 3 ⁴ is H, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluoromethyl, difluoromethyl, trifluoro Methoxy, amino, N, N-dimethylamino, N, N-diethylamino, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N- (2-furylmethyl) a Nosulfonyl, nitro, N, N-dimethylaminosulfonyl, aminosulfonyl, N-methylaminosulfonyl, N-ethylsulfonyl, 2,2-dimethylethylaminosulfonyl, N, N-dimethylaminosulfonyl, N- (2-methyl) Propyl) aminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl or phenyl; or wherein R ⁴ is the carbon atom to which it is attached and the ring E Forms a naphthyl radical with the remainder;
It can also be a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.

Cyclooxygenase-2 selective inhibitors further include:
n is an integer of 0, 1, 2, 3 or 4;
R ³ is trifluoromethyl or pentafluoroethyl; and each R ⁴ is independently H, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, tri Fluoromethoxy, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N- (2-furylmethyl) aminosulfonyl, N, N-dimethylaminosulfonyl, N-methylaminosulfonyl, N- (2,2-dimethyl) Ethyl) aminosulfonyl, dimethylaminosulfonyl, 2-methylpropylaminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, or phenyl; or wherein R ⁴ is the carbon atom to which it is attached and the ring E The rest of Together with the formation of a naphthyl radical;
It can also be a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.

In yet another embodiment, the cyclooxygenase-2 selective inhibitor used in connection with the method of the present invention further comprises:
n = 4;
G is O or S;
R ¹ is H;
R ² is CO ₂ H;
R ³ is lower haloalkyl;
The first R ⁴ corresponding to R ⁹ is hydride or halo;
The second R ⁴ corresponding to R ¹⁰ is H, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower alkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl. 5-membered nitrogen-containing heterocyclosulfonyl, or 6-membered nitrogen-containing heterocyclosulfonyl;
A third R ⁴ corresponding to R ¹¹ is H, lower alkyl, halo, lower alkoxy, or aryl; and a fourth R ⁴ corresponding to R ¹² is H, halo, lower alkyl, lower alkoxy, And aryl;
Can be a compound having the structure of formula (I), or a pharmaceutically acceptable salt or prodrug thereof,
Here, the formula (I) is represented by the following formula (Ia):

Represented by
The cyclooxygenase-2 selective inhibitor used in connection with the method of the present invention further comprises:
R ⁸ is trifluoromethyl or pentafluoroethyl;
R ⁹ is H, chloro, or fluoro;
R ¹⁰ is H, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, benzylaminosulfonyl, phenylethylaminosulfonyl, Methylpropylaminosulfonyl, methylsulfonyl, or morpholinosulfonyl;
R ¹¹ is H, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, or phenyl; and R ¹² is H, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, Or phenyl;
It can also be a compound having the structure of formula (Ia), or a pharmaceutically acceptable salt or prodrug thereof.

  Examples of exemplary chromene cyclooxygenase-2 selective inhibitors are depicted in Table 1x below.

  In a further embodiment, the cyclooxygenase-2 selective inhibitor or pharmaceutically acceptable salt or prodrug thereof has the following formula II:

Wherein A is selected from the group consisting of a partially unsaturated or unsaturated heterocyclyl and a partially unsaturated or unsaturated carbocyclic ring;
Wherein R ¹ is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R ¹ is alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkyl Optionally substituted at a substitutable position with one or more radicals selected from amino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
Wherein R ² is selected from the group consisting of methyl or amino; and wherein R ³ is H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, Alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, Aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aralkyl Nocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N -Aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylamino Alkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, Reel sulfonyl is selected from the group consisting of radicals chosen from N- alkyl -N- arylaminosulfonyl;]
Selected from the group of tricyclic cyclooxygenase-2 selective inhibitors represented by the general structure: or a pharmaceutically acceptable salt thereof.

  In another embodiment, the cyclooxygenase-2 selective inhibitor represented by Formula II above, or a pharmaceutically acceptable salt or prodrug thereof, is celecoxib (B-18; US Pat. No. 5,466,823). CAS number 169,590-42-5), valdecoxib (B-19; U.S. Pat. No. 5,633,272; CAS number 181695-72-7), deracoxib (B-20); 521,207; CAS number 169590-41-4), rofecoxib (B-21; CAS number 162011-90-7), etoroxib (MK-663; B-22; PCT application publication WO 98/03484), JTE-522 A group of compounds exemplified in Table 2x consisting of (B-23) or a pharmaceutical thereof It is selected from acceptable salt or prodrug thereof.

In yet another embodiment, the cyclooxygenase-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib and etoricoxib.
In yet another embodiment, the cyclooxygenase-2 selective inhibitor has the following formula:

Of parecoxib (B-24, US Pat. No. 5,932,598, CAS No. 198470-84-7), which is therapeutically effective for the tricyclic cyclooxygenase-2 selective inhibitor valdecoxib, B-19. It is an effective prodrug and can be conveniently used as a source of cyclooxygenase inhibitors (US Pat. No. 5,932,598, incorporated herein by reference).

One form of parecoxib is sodium parecoxib.
In another preferred embodiment of the present invention, the following formula B-25, previously described in International Patent Application Publication No. WO 00/24719, which is incorporated herein by reference:

Is another tricyclic cyclooxygenase-2 selective inhibitor that can be used conveniently.
Another cyclooxygenase-2 selective inhibitor useful in connection with the methods of the present invention is the following formula B-26:

N- (2-cyclohexyloxynitrophenyl) methanesulfonamide (NS-398) having the structure shown as
In a still further aspect, the cyclooxygenase-2 selective inhibitor or pharmaceutically acceptable salt or prodrug thereof used in connection with the method of the present invention has the following formula (III):

[Where:
R ¹⁶ is methyl or ethyl;
R ¹⁷ is chloro or fluoro;
R ¹⁸ is hydrogen or fluoro;
R ¹⁹ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy;
R ²⁰ is hydrogen or fluoro; and R ²¹ is chloro, fluoro, trifluoromethyl or methyl;
Provided that when R ¹⁶ is ethyl and R ¹⁹ is H, R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are not all fluoro;
The phenylacetic acid derivative represented by the general structure can be selected from the group of cyclooxygenase-2 selective inhibitors.

Another phenylacetic acid derivative cyclooxygenase-2 selective inhibitor used in connection with the method of the present invention has the name COX 189 (B-211) and has the structure shown in formula (III) A compound or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R ¹⁶ is ethyl;
R ¹⁷ and R ¹⁹ are chloro;
R ¹⁸ and R ²⁰ are hydrogen; and R ²¹ is methyl.

  In yet another embodiment, the cyclooxygenase-2 selective inhibitor or pharmaceutically acceptable salt or prodrug thereof has the following formula (IV):

[Where:
X is O or S;
J is a carbocyclic or heterocyclic ring;
R ²² is NHSO ₂ CH ₃ or F;
R ²³ is H, NO ₂ , or F; and R ²⁴ is H, NHSO ₂ CH ₃ , or (SO ₂ CH ₃ ) C ₆ H ₄ ;]
Represented by

  According to another embodiment, the cyclooxygenase-2 selective inhibitor or pharmaceutically acceptable salt or prodrug thereof used in the method of the present invention has the following structural formula (V):

Wherein T and M are independently a radical derived from a heterocycle containing phenyl, naphthyl, 5 to 6 members and carrying 1 to 4 heteroatoms, or 3 to 7 A radical derived from a saturated hydrocarbon ring having one carbon atom;
Q ¹ , Q ² , L ¹ or L ² is independently hydrogen, halogen, lower alkyl having 1 to 6 carbon atoms, trifluoromethyl, or lower methoxy having 1 to 6 carbon atoms; And at least one of Q ¹ , Q ² , L ¹ or L ² is in the para position and is —S (O) _n —R, wherein n is 0, 1, or 2, and R is 1 or to a lower haloalkyl radical or -SO ₂ NH ₂ with a lower alkyl radical or 1 to 6 carbon atoms having 6 carbon atoms; or
Q ¹ and Q ² are methylenedioxy; or L ¹ and L ² are methylenedioxy; and R ²⁵ , R ²⁶ , R ²⁷ , and R ²⁸ are independently hydrogen, halogen, 1 Is a lower alkyl having 6 to 6 carbon atoms, a lower haloalkyl having 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl; or R ²⁵ And R ²⁶ is O; or R ²⁷ and R ²⁸ are O; or R ²⁵ and R ²⁶ are 3 to 7 carbon atoms together with the carbon atom to which they are connected. saturated charcoal or R ^27, R ²⁸ are, together with the carbon atoms to which they are attached, having from 3 to 7 carbon atoms; saturated or form a hydrocarbon ring having Form a hydrocarbon ring.

  In another embodiment, a compound having the structure of formula (V), N- (2-cyclohexyloxynitrophenyl) methanesulfonamide, and (E) -4-[(4-methylphenyl) (tetrahydro-2-oxo -3-Furanylidene) methyl] benzenesulfonamide is used as a cyclooxygenase-2 selective inhibitor.

In a further aspect, compounds useful for cyclooxygenase-2 selective inhibitors or pharmaceutically acceptable salts or prodrugs thereof associated with the methods of the invention, the structures of which are listed in Table 3x below Includes but is not limited to:
6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-27);
6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-28);
8- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-29);
6-chloro-8- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-30);
2-trifluoromethyl-3H-naphtho [2,1-b] pyran-3-carboxylic acid (B-31);
7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-32);
6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-33);
8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-34);
6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-35);
5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-36);
8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-37);
7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-38);
6,8-bis (dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-39);
7- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-40);
7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-41);
6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-42);
6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-43);
6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-44);
6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-45);
6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-46);
6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-47);
8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-48);
8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-49);
6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-50);
8-Bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-51);
8-Bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-52);
8-Bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-53);
6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-54);
6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-55);
6-[[(Phenylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-56);
6-[(dimethylamino) sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-57);
6-[(methylamino) sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-58);
6-[(4-morpholino) sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-59);
6-[(1,1-dimethylethyl) aminosulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-60);
6-[(2-methylpropyl) aminosulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-61);
6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-62);
8-chloro-6-[[(phenylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-63);
6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-64);
6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-65);
8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-66);
6,8-dichloro- (S) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-67);
6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-68);
6-[[N- (2-furylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-69);
6-[[N- (2-phenylethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-70);
6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-71);
7- (1,1-dimethylethyl) -2-pentafluoroethyl-2H-1-benzopyran-3-carboxylic acid (B-72);
6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid (B-73);
3-[(3-chloro-phenyl)-(4-methanesulfonyl-phenyl) -methylene] -dihydro-furan-2-one or BMS-347070 (B-74);
8-acetyl-3- (4-fluorophenyl) -2- (4-methylsulfonyl) phenyl-imidazo (1,2-a) pyridine (B-75);
5,5-dimethyl-4- (4-methylsulfonyl) phenyl-3-phenyl-2- (5H) -furanone (B-76);
5- (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazole (B-77);
4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) pyrazole (B-78);
4- (5- (4-chlorophenyl) -3- (4-methoxyphenyl) -1H-pyrazol-1-yl) benzenesulfonamide (B-79);
4- (3,5-bis (4-methylphenyl) -1H-pyrazol-1-yl) benzenesulfonamide (B-80);
4- (5- (4-chlorophenyl) -3-phenyl-1H-pyrazol-1-yl) benzenesulfonamide (B-81);
4- (3,5-bis (4-methoxyphenyl) -1H-pyrazol-1-yl) benzenesulfonamide (B-82);
4- (5- (4-chlorophenyl) -3- (4-methylphenyl) -1H-pyrazol-1-yl) benzenesulfonamide (B-83);
4- (5- (4-chlorophenyl) -3- (4-nitrophenyl) -1H-pyrazol-1-yl) benzenesulfonamide (B-84);
4- (5- (4-chlorophenyl) -3- (5-chloro-2-thienyl) -1H-pyrazol-1-yl) benzenesulfonamide (B-85);
4- (4-chloro-3,5-diphenyl-1H-pyrazol-1-yl) benzenesulfonamide (B-86);
4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-87);
4- [5-phenyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-88);
4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-89);
4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-90);
4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-91);
4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-92);
4- [4-chloro-5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-93);
4- [3- (difluoromethyl) -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-94);
4- [3- (difluoromethyl) -5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide (B-95);
4- [3- (difluoromethyl) -5- (4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-96);
4- [3-cyano-5- (4-fluorophenyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-97);
4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-98);
4- [5- (3-Fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-99);
4- [4-chloro-5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide (B-100);
4- [5- (4-chlorophenyl) -3- (hydroxymethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-101);
4- [5- (4- (N, N-dimethylamino) phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-102);
5- (4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene (B-103);
4- [6- (4-fluorophenyl) spiro [2.4] hept-5-en-5-yl] benzenesulfonamide (B-104);
6- (4-Fluorophenyl) -7- [4- (methylsulfonyl) phenyl] spiro [3.4] oct-6-ene (B-105);
5- (3-chloro-4-methoxyphenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene (B-106);
4- [6- (3-Chloro-4-methoxyphenyl) spiro [2.4] hept-5-en-5-yl] benzenesulfonamide (B-107);
5- (3,5-dichloro-4-methoxyphenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene (B-108);
5- (3-chloro-4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene (B-109);
4- [6- (3,4-dichlorophenyl) spiro [2.4] hept-5-en-5-yl] benzenesulfonamide (B-110);
2- (3-chloro-4-fluorophenyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) thiazole (B-111);
2- (2-chlorophenyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) thiazole (B-112);
5- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-methylthiazole (B-113);
4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2-trifluoromethylthiazole (B-114);
4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2- (2-thienyl) thiazole (B-115);
4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2-benzylaminothiazole (B-116);
4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2- (1-propylamino) thiazole (B-117);
2-[(3,5-dichlorophenoxy) methyl) -4- (4-fluorophenyl-5- [4- (methylsulfonyl) phenyl] thiazole (B-118);
5- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-trifluoromethylthiazole (B-119);
1-methylsulfonyl-4- [1,1-dimethyl-4- (4-fluorophenyl) cyclopenta-2,4-dien-3-yl] benzene (B-120);
4- [4- (4-fluorophenyl) -1,1-dimethylcyclopenta-2,4-dien-3-yl] benzenesulfonamide (B-121);
5- (4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hepta-4,6-diene (B-122);
4- [6- (4-fluorophenyl) spiro [2.4] hepta-4,6-dien-5-yl] benzenesulfonamide (B-123);
6- (4-Fluorophenyl) -2-methoxy-5- [4- (methylsulfonyl) phenyl] -pyridine-3-carbonitrile (B-124);
2-Bromo-6- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -pyridine-3-carbonitrile (B-125);
6- (4-Fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-phenyl-pyridine-3-carbonitrile (B-126);
4- [2- (4-methylpyridin-2-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-127);
4- [2- (5-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-128);
4- [2- (2-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-129);
3- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine (B-130);
2- [1- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine (B-131);
2-methyl-4- [1- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine (B-132);
2-methyl-6- [1- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine (B-133);
4- [2- (6-Methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-134);
2- (3,4-difluorophenyl) -1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazole (B-135);
4- [2- (4-methylphenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-136);
2- (4-chlorophenyl) -1- [4- (methylsulfonyl) phenyl] -4-methyl-1H-imidazole (B-137);
2- (4-chlorophenyl) -1- [4- (methylsulfonyl) phenyl] -4-phenyl-1H-imidazole (B-138);
2- (4-chlorophenyl) -4- (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -1H-imidazole (B-139);
2- (3-Fluoro-4-methoxyphenyl) -1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazole (B-140);
1- [4- (methylsulfonyl) phenyl] -2-phenyl-4-trifluoromethyl-1H-imidazole (B-141);
2- (4-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazole (B-142);
4- [2- (3-chloro-4-methylphenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-143);
2- (3-Fluoro-5-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazole (B-144);
4- [2- (3-Fluoro-5-methylphenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-145);
2- (3-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazole (B-146);
4- [2- (3-methylphenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide (B-147);
1- [4- (methylsulfonyl) phenyl] -2- (3-chlorophenyl) -4-trifluoromethyl-1H-imidazole (B-148);
4- [2- (3-chlorophenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide (B-149);
4- [2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide (B-150);
4- [2- (4-Methoxy-3-chlorophenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide (B-151);
1-allyl-4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazole (B-152);
4- [1-ethyl-4- (4-fluorophenyl) -5- (trifluoromethyl) -1H-pyrazol-3-yl] benzenesulfonamide (B-153);
N-phenyl- [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazol-1-yl] acetamide (B-154);
[4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazol-1-yl] ethyl acetate (B-155);
4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -1- (2-phenylethyl) -1H-pyrazole (B-156);
4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -1- (2-phenylethyl) -5- (trifluoromethyl) pyrazole (B-157);
1-ethyl-4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazole (B-158);
5- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-trifluoromethyl-1H-imidazole (B-159);
4- [4- (methylsulfonyl) phenyl] -5- (2-thiophenyl) -2- (trifluoromethyl) -1H-imidazole (B-160);
5- (4-fluorophenyl) -2-methoxy-4- [4- (methylsulfonyl) phenyl] -6- (trifluoromethyl) pyridine (B-161);
2-Ethoxy-5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -6- (trifluoromethyl) pyridine (B-162);
5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -2- (2-propynyloxy) -6- (trifluoromethyl) pyridine (B-163);
2-Bromo-5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -6- (trifluoromethyl) pyridine (B-164);
4- [2- (3-chloro-4-methoxyphenyl) -4,5-difluorophenyl] benzenesulfonamide (B-165);
1- (4-fluorophenyl) -2- [4- (methylsulfonyl) phenyl] benzene (B-166);
5-difluoromethyl-4- (4-methylsulfonylphenyl) -3-phenylisoxazole (B-167);
4- [3-ethyl-5-phenylisoxazol-4-yl] benzenesulfonamide (B-168);
4- [5-difluoromethyl-3-phenylisoxazol-4-yl] benzenesulfonamide (B-169);
4- [5-hydroxymethyl-3-phenylisoxazol-4-yl] benzenesulfonamide (B-170);
4- [5-Methyl-3-phenyl-isoxazol-4-yl] benzenesulfonamide (B-171);
1- [2- (4-fluorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-172);
1- [2- (4-fluoro-2-methylphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-173);
1- [2- (4-chlorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-174);
1- [2- (2,4-dichlorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-175);
1- [2- (4-trifluoromethylphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-176);
1- [2- (4-methylthiophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-177);
1- [2- (4-fluorophenyl) -4,4-dimethylcyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-178);
4- [2- (4-fluorophenyl) -4,4-dimethylcyclopenten-1-yl] benzenesulfonamide (B-179);
1- [2- (4-chlorophenyl) -4,4-dimethylcyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-180);
4- [2- (4-chlorophenyl) -4,4-dimethylcyclopenten-1-yl] benzenesulfonamide (B-181);
4- [2- (4-fluorophenyl) cyclopenten-1-yl] benzenesulfonamide (B-182);
4- [2- (4-chlorophenyl) cyclopenten-1-yl] benzenesulfonamide (B-183);
1- [2- (4-methoxyphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-184);
1- [2- (2,3-difluorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-185);
4- [2- (3-Fluoro-4-methoxyphenyl) cyclopenten-1-yl] benzenesulfonamide (B-186);
1- [2- (3-chloro-4-methoxyphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-187);
4- [2- (3-chloro-4-fluorophenyl) cyclopenten-1-yl] benzenesulfonamide (B-188);
4- [2- (2-methylpyridin-5-yl) cyclopenten-1-yl] benzenesulfonamide (B-189);
2- [4- (4-Fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazol-2-yl] -2-benzyl-ethyl acetate (B-190);
2- [4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazol-2-yl] acetic acid (B-191);
2- (tert-butyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazole (B-192);
4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-phenyloxazole (B-193);
4- (4-fluorophenyl) -2-methyl-5- [4- (methylsulfonyl) phenyl] oxazole (B-194);
4- [5- (3-Fluoro-4-methoxyphenyl) -2-trifluoromethyl-4-oxazolyl] benzenesulfonamide (B-195);
6-chloro-7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-196);
6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-197);
5,5-dimethyl-3- (3-fluorophenyl) -4-methylsulfonyl-2 (5H) -furanone (B-198);
6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid (B-199);
4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-200);
4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-201);
4- [5- (3-Fluoro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-202);
3- [1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazol-2-yl] pyridine (B-203);
2-methyl-5- [1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazol-2-yl] pyridine (B-204);
4- [2- (5-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-205);
4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide (B-206);
4- [5-hydroxymethyl-3-phenylisoxazol-4-yl] benzenesulfonamide (B-207);
[2-trifluoromethyl-5- (3,4-difluorophenyl) -4-oxazolyl] benzenesulfonamide (B-208);
4- [2-methyl-4-phenyl-5-oxazolyl] benzenesulfonamide (B-209);
4- [5- (2-fluoro-4-methoxyphenyl) -2-trifluoromethyl-4-oxazolyl] benzenesulfonamide (B-210);
[2- (2-Chloro-6-fluoro-phenylamino) -5-methyl-phenyl] -acetic acid or COX 189 (B-211);
N- (4-nitro-2-phenoxy-phenyl) methanesulfonamide or nimesulide (B-212);
N- [6- (2,4-difluoro-phenoxy) -1-oxo-indan-5-yl] -methanesulfonamide or flosulide (B-213);
N- [6- (2,4-difluoro-phenylsulfanyl) -1-oxo-1H-inden-5-yl] -methanesulfonamide, sodium salt or L-745337 (B-214);
N- [5- (4-Fluoro-phenylsulfanyl) -thiophen-2-yl] methanesulfonamide or RWJ-63556 (B-215);
3- (3,4-difluoro-phenyl) -4- (4-methanesulfonyl-phenyl) -5-methyl-5- (2,2,2-trifluoro-ethyl) -5H-furan-2-one or L-784512 or L-784512 (B-216);
(5Z) -2-Amino-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4 (5H) -thiazolone or darbuferone (B-217) ;
CS-502 (B-218);
LAS-34475 (B-219);
LAS-34555 (B-220);
S-33516 (B-221);
SD-8381 (B-222);
L-783003 (B-223);
N- [3- (formylamino) -4-oxo-6-phenoxy-4H-1-benzopyran-7-yl] methanesulfonamide or T-614 (B-224);
D-1367 (B-225);
L-748731 (B-226);
(6aR, 10aR) -3- (1,1-dimethylheptyl) -6a, 7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo [b, d] pyran-9-carvone Acid or CT3 (B-277);
CGP-28238 (B-228);
4-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] dihydro-2-methyl-2H-1,2-oxazin-3 (4H) -one or BF-389 ( B-229);
GR-253035 (B-230);
6-Dioxo-9H-purin-8-yl-cinnamic acid (B-231);
S-2427 (B-232);
4- [4- (methyl) -sulfonyl) phenyl] -3-phenyl-2 (5H) -furanone;
4- (5-methyl-3-phenyl-4-isoxazolyl);
2- (6-methylpyrid-3-yl) -3- (4-methylsulfonylphenyl) -5-chloropyridine;
4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl];
N-[[4- (5-Methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonyl];
4- [5- (3-Fluoro-4-methoxyphenyl) -3-difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
(S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid;
2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone;
2-trifluoromethyl-3H-naphtho [2,1-b] pyran-3-carboxylic acid;
6-chloro-7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
[2- (2,4-Dichloro-6-ethyl-3,5-dimethyl-phenamino) -5-propyl-phenyl] -acetic acid.

  The cyclooxygenase-2 selective inhibitors used in the present invention can exist in tautomeric, geometric or stereoisomeric forms. Generally speaking, a suitable cyclooxygenase-2 selective inhibitor that is in a tautomeric, geometric or stereoisomeric form, when present at a concentration of 100 μM or less, reduces cyclooxygenase-2 activity by about 25%. More typically about 50%, and even more typically compounds that inhibit about 75% or more. The present invention relates to cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereoisomers, d-isomers, l-isomers, and racemic mixtures thereof. And all such compounds including these and other mixtures thereof are contemplated. Such tautomeric, geometric or stereoisomeric forms of pharmaceutically acceptable salts are further included in the present invention. As used herein, the terms “cis” and “trans” refer to two carbon atoms connected by a double bond, each hydrogen atom on the same side of the double bond (“cis”), Or it refers to a form of geometric isomerism that is on the opposite side ("trans") of a double bond. Some of the compounds described contain alkenyl groups and are meant to include both cis and trans or “E” and “Z” geometric forms. Further, some of the compounds described contain one or more stereocenters and include, for each existing stereocenter, R, S, and mixtures or R and S forms. means.

  The cyclooxygenase-2 selective inhibitor used in the present invention can be in the form of the free base or a pharmaceutically acceptable acid addition salt thereof. The term “pharmaceutically acceptable salt” is a salt commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt can vary, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds for use in the methods of the present invention can be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acids can be selected from the group of organic acids aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic acid and sulfonic acid, examples of which are formic acid, acetic acid, propion Acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamo acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylamino Sulfonic acid, stearic acid, argenic acid, hydroxybutyric acid, salic Le acid, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of the compounds used in the methods of the present invention are metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or N, N′-dibenzyl Includes organic salts made from ethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All such salts can be prepared from the corresponding compound by conventional means, for example by reacting the appropriate acid or base with any of the compounds of the formulas described herein.

  The cyclooxygenase-2 selective inhibitor useful in the practice of the present invention can be administered by any means that is formulated into a pharmaceutical composition and releases a therapeutically effective dose. Such compositions can be administered orally, parenterally, by inhalation spray, rectally, intradermally, transdermally or topically, optionally with conventional skin toxic pharmaceuticals. It can be administered in dosage unit formulations containing an acceptable carrier, an adjuvant, and a vehicle. Topical administration is also included in the use of transdermal administration such as transdermal patches or iontophoretic devices. As used herein, the term parenteral includes subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques. Drug prescriptions are described, for example, in Hoover, John E. et al. , Remington's Pharmaceutical Science, Mack Publishing Co. , Easton, Pennsylvania (1975), and Liberman, H .; A. and Lachman, L .; Eds. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N .; Y. (1980).

  Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are useful in the preparation of injectables. Dimethylacetamide, surfactants containing ionic or non-ionic detergents, and polypropylene glycol can be used. Also useful are mixtures of solvents and wetting agents as discussed above.

  Suppositories for rectal administration of the compounds discussed herein are active agents that are solid at normal temperature, but liquid at rectal temperature, and therefore melt in the rectum, and the drug Can be prepared by mixing with a suitable nonirritating excipient such as cocoa butter, synthetic mono-, di- or triglycerides, fatty acids or polyethylene glycols.

  Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound is usually mixed with one or more adjuvants appropriate to the indicated route of administration. When administered orally, the compounds include lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, It can be mixed with gelatin, gum arabic, sodium alginate, polyvinyl pyrrolidone, and / or polyvinyl alcohol and then tableted or encapsulated for convenient administration. Such capsules and tablets can contain controlled release formulations, such as can be obtained with dispersions of the active compound in hydroxypropylmethylcellulose. In the case of capsules, tablets and pills, the dosage forms may further comprise sodium citrate or a buffering agent such as carbonate or magnesium bicarbonate or calcium. Tablets and pills can additionally be prepared with enteric coatings.

  For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents described for use in formulations for oral administration. The compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Can be included. Such compositions may further comprise wetting agents, emulsifying and suspending agents, and adjuvants such as sweetening, flavoring and fragrances.

  The amount of active ingredient that can be combined with a carrier material to produce a single dosage of the cyclooxygenase-2 selective inhibitor will vary depending on the patient and the particular mode of administration. Generally, the pharmaceutical composition is in the range of about 0.1 to 2000 mg, more typically in the range of about 0.5 to 500 mg, and even more typically between about 1 and 200 mg of cyclooxygenase-2. Selective inhibitors can be included. A daily dose of about 0.01 to 100 mg / kg body weight, or more typically about 0.1 to about 50 mg / kg body weight, and even more typically about 1 to 20 mg / kg body weight is suitable. Can be. The daily dose can be administered 1 to 4 times per day.

  In one embodiment, when the cyclooxygenase-2 selective inhibitor comprises rofecoxib, typically the amount used is in the range of about 0.15 to about 1.0 mg / day · kg; And still more typically, from about 0.18 to about 0.4 mg / day · kg.

  In yet another embodiment, when the cyclooxygenase-2 selective inhibitor comprises etoroxib, typically the amount used is in the range of about 0.5 to about 5 mg / day · kg, And still more typically, from about 0.8 to about 4 mg / day · kg.

  Further, when the cyclooxygenase-2 selective inhibitor comprises celecoxib, the amount used is in the range of about 1 to about 20 mg / day · kg, and still more typically about 1.4 to About 8.6 mg / day · kg, and even more typically about 2 to about 3 mg / day · kg.

  When the cyclooxygenase-2 selective inhibitor comprises valdecoxib, the amount used is in the range of about 0.1 to about 5 mg / day · kg, and still more typically about 0.8 to About 4 mg / day · kg.

  In a further embodiment, when the cyclooxygenase-2 selective inhibitor comprises parecoxib, the amount used is in the range of about 0.1 to about 5 mg / day · kg, and even more typically About 1 to about 3 mg / day · kg.

Those skilled in the art can further determine the dosages from Goodman &Goldman's The Pharmaceutical Basis of Therapeutics , Ninth Edition (1996), Appendix II, pp. 1707-1711 and Goodman &Goldman's The Pharmacological Basis of Therapeutics , Tenth Edition (2001), Appendix II, pp. Pp. 199-001 . It will also be recognized that it can be determined from the guidance of 475-493.

Carbonic Anhydrase Inhibitors Many suitable carbonic anhydrase inhibitors, or pharmaceutically acceptable salts or prodrugs thereof, can be used in the methods of the present invention. Typically, the carbonic anhydrase inhibitor used does not inhibit cyclooxygenase-2. In one embodiment, the carbonic anhydrase inhibitor can be, for example, metazolamide, Formula A-1 (CAS Registry Number 554-57-4), or a pharmaceutically acceptable salt or prodrug thereof. :

  In another embodiment, the carbonic anhydrase inhibitor can be, for example, acetazolamide, Formula A-2 (CAS Registry Number 59-66-5), or a pharmaceutically acceptable salt or prodrug thereof.

  In yet another embodiment, the carbonic anhydrase inhibitor can be, for example, diclofenamide, Formula A-3 (CAS Registry Number 120-97-8), or a pharmaceutically acceptable salt or prodrug thereof. it can.

  In a further embodiment, the carbonic anhydrase inhibitor consists of a benzothiazole sulfonamide having the general formula I shown below and by way of example and not limitation, having the structure disclosed in Table 1 Selected from the group. In addition, benzothiazole sulfonamide carbonic anhydrase inhibitors useful in the practice of the methods of the invention are described in US Pat. Nos. 4,975,449 and 5,059,613, both of which are All of which are incorporated herein by reference.

In the formula:
Each R ₁ is hydrogen, lower alkyl, halogen, nitro, trihaloalkyl, lower alkoxy, formyl, lower alkanoyl lower alkylamino or di-lower alkylamino;
R ₆ is hydrogen or lower alkyl;
Y ₁ represents the following formula:

And in the formula:
X ₁ is O or NR ₅ or S;
R ₂ is OR ₇ or NR ₇ R ₈ ;
Each R ₃ and R ₄ is hydrogen or lower alkyl;
R ₅ , R ₇ and R ₈ are independently hydrogen or lower alkyl;
m is an integer that is 0, 1, 2, 3, 4, 5, or 6; and n is an integer that is 0, 1, 2, or 3.

  In another embodiment, the carbonic anhydrase inhibitor is represented by the general structure of Formula IIa shown below, and by way of example and not limitation, a benzothiazole possessing the structure disclosed in Table 2a: Selected from the group of sulfonamide carbonic anhydrase inhibitors. In addition, benzothiazole sulfonamide carbonic anhydrase inhibitors useful in the practice of the methods of the invention are described in US Pat. Nos. 5,095,026 and 5,157,044, both of which are All of which are incorporated by reference in the specification.

In the formula:
Z ₁ represents a water-soluble carrier, and A ₁ still possesses carbonic anhydrase inhibitory activity, but further forms an enzymatically cleavable bond between A ₁ and Z _1. It is the part that connects to the carbonic anhydrase inhibitor that enables.

  In yet another embodiment, the carbonic anhydrase inhibitor is represented by the general structure of Formula IIb shown below and retains the structure disclosed in Table 2b by way of example and not limitation: Selected from the group of hydroxymetazolamido carbonic anhydrase inhibitors. In addition, hydroxymetazolamide carbonic anhydrase inhibitors useful in the practice of the methods of the invention are described in US Pat. Nos. 5,095,026 and 5,157,044, both of which All of which are incorporated by reference in the specification.

In the formula:
Z ₂ represents a water-soluble carrier,
n is 1, 2, 3, 4, or a 5; and A _2, This is to still retain the carbonic anhydrase inhibition activity, but an enzymatically cleavable bond between _{A 2} and _{Z 2} The part connected to the carbonic anhydrase inhibitor that also makes it possible to form.

  In yet another embodiment, the carbonic anhydrase inhibitor is represented by the general structure of Formula IIc shown below, and by way of example and not limitation, the dichlorophenamide carbonic disclosed in Table 2c: Selected from the group of anhydrase inhibitors. In addition, dichlorophenamide carbonic anhydrase inhibitors useful in the practice of the methods of the invention are described in US Pat. Nos. 5,095,026 and 5,157,044, both of which are described herein. All of which are incorporated by reference in the book.

In the formula:
Z ₃ represents a water-soluble carrier; and A ₃ still possesses carbonic anhydrase inhibitory activity, but also forms an enzymatically cleavable bond between A ₃ and Z _3. The part that connects to the carbonic anhydrase inhibitor that enables.

  In yet another embodiment, the carbonic anhydrase inhibitor is represented by the general structure of Formula III shown below, and by way of example and not limitation, the metazolamide carbonic disclosed in Table 3 Selected from the group of anhydrase inhibitors. Furthermore, metazolamide carbonic anhydrase inhibitors useful in the practice of the methods of the invention are described in US Pat. No. 5,104,887, both of which are incorporated herein by reference. Everything is incorporated.

In the formula:
n is an integer that is 0, 1, 2, 3, 4, or 5;
X ₂ is hydrogen, hydroxyl, hydroxylmethyl, 2-hydroxyethyl, or 2-hydroxyethoxy;
Ar ₁ is phenyl, pyridyl, or furanyl; and m is an integer that is 0, 1, 2, 3, or 4.

  In another embodiment, the carbonic anhydrase inhibitor is represented by the general structure of Formula IV shown below, and by way of example and not limitation, the thiophenesulfonamido carbonic acids disclosed in Table 4: Selected from the group of hydrase inhibitors. In addition, thiophene sulfonamide carbonic anhydrase inhibitors useful in the practice of the methods of the present invention are described in US Pat. Nos. 5,153,192, 5,240,923, 5,378,703, and 5,620. , 970, all of which are incorporated herein by reference in their entirety.

In the formula:
R ₉ is H, C _1-4 alkyl, C _2-4 alkyl optionally substituted with OH, halogen, C _1-4 alkoxy, or C (═O) R ₁₅ ;
R ₁₀ is H; C _1-8 alkyl, OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C _2-8 alkyl substituted with C (═O) R ₁₅ ; C _3-7 alkenyl optionally substituted with OH, NR ₁₃ R ₁₄ , or C _1-4 alkoxy; unsubstituted or optionally substituted with OH, NR ₁₃ R ₁₄ , or C _1-4 alkoxy C _3-7 alkynyl; unsubstituted or optionally OH, (CH ₂ ) _n NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₁₅ , S (═O) _m R ₁₆ , or C _1-3 alkyl substituted with phenyl or heteroaryl, which can be substituted with SO ₂ NR ₁₃ R ₁₄ , where m Is 0-2 and n is 0-2; C _2-4 alkoxy optionally substituted with NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy, or C (═O) R ₁₅ ; OH, (CH ₂ ) _n NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₁₅ , S (═O) _m R ₁₆ Or phenyl substituted by SO ₂ NR ₁₃ R ₁₄ , or heteroaryl, where m is 0-2 and n is 0-2; provided that both R ₉ and R ₁₀ are H Or R ₉ and R ₁₀ can be joined to form a saturated ring of 5 or 6 atoms selected from O, S, C or N, which is Not replaced or replaced OH on carbon _{by, NR} 13 _{R 14, halogen, C 1-4 alkoxy, C (= O) R 15} , C 1-6 alkyl, optionally _{OH, NR} 13 _{R 14, halogen, C 1-4} alkoxy, C (= _O) by _{C 1-6} alkyl substituted with _{R 15,} or a nitrogen _NR 13 _{R 14, C 1-4 alkoxy, C (= O) R 15} , C 1-6 alkyl or optionally OH, NR Can be substituted with C _2-6 alkyl substituted with ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R ₁₅ ;
R ₁₁ is H; halogen; C _1-4 alkyl; C _1-8 alkoxy; C _1-8 alkyl thiol; optionally OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R C _2-8 alkoxy substituted with ₁₅ ; C _1-4 alkyl optionally substituted with R ₁₂ ; or R ₉ and R ₁₁ are joined together with a carbon atom to form a 5- to 7-membered ring Wherein the carbon atom can be unsubstituted or optionally substituted with R ₁₂ ;
R ₁₂ is OH; C _1-4 alkyl, unsubstituted or optionally substituted with OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R ₁₅ ; C _1-4 Alkoxy; C _2-4 alkoxy optionally substituted with OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R ₁₅ ; NR ₁₃ R ₁₄ ; unsubstituted or optionally OH , (CH ₂ ) _n NR ₁₃ R ₁₄ , substituted with halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₁₅ , S (═O) R ₁₆ or SO ₂ NR ₁₃ R ₁₄ Phenyl or heteroaryl, wherein m is 0-2 and n is 0-2;
R ₁₃ and R ₁₄ are the same or different and are H; C _1-4 alkyl; C _2-4 alkyl optionally substituted with OH, halogen, C _1-4 alkoxy or C (═O) R ₁₅ C _1-4 alkoxy; C _2-4 alkoxy optionally substituted with OH, halogen, C _1-4 alkoxy or C (═O) R ₁₅ ; unsubstituted or optionally OH, NR ₁₃ R _14; , or _{C 1-4 C 3-7} alkenyl substituted by alkoxy; unsubstituted or optionally _{OH, NR} 13 _{R 14,} or _{C 3-7} alkynyl substituted with _{C 1-4} alkoxy; _{C 1} There _-2 alkyl _{C 3-5} cycloalkyl; or _{R 13} and _{R 14} are bonded, to form O, S, a 5- or 6 atoms selected from C or N Can, which is either unsubstituted or optionally OH at carbon, (= O), OH _{halogen, C 1-4 alkoxy, C (= O) R 15} , C 1-6 alkyl, optionally halogen , C _1-4 alkoxy, C _1-6 alkyl substituted with C (═O) R ₁₅ , or at nitrogen, C _1-4 alkoxy, C (═O) R ₁₅ , S (═O) _m R ₁₆ , C _1-6 alkyl or optionally substituted with OH, halogen, C _1-4 alkoxy, C _2-6 alkyl substituted with C (═O) R ₁₅ , or in sulfur with (═O) _m Where m is 0-2;
R _{15 is, C 1-8} alkyl; optionally _{OH, NR} 13 _{R 14, halogen, C 1-4} alkoxy or _C (= _O) C substituted with _{R 17 1-8 alkyl; C 1-4} alkoxy; C _2-4 alkoxy optionally substituted with OH, NR ₁₃ R ₁₄ , halogen or C _1-4 alkoxy; or NR ₁₃ R ₁₄ ;
R ₁₆ is C _1-4 alkyl; optionally C _2-4 alkyl substituted with OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R ₁₅ ; and R ₁₇ is C _1-4 alkyl; C _1-4 alkoxy; amino, C _1-3 alkylamino, or di-C _1-3 alkylamino; and G ₁ is C (═O) or SO ₂ .

  In yet another embodiment, the carbonic anhydrase inhibitor is represented by the general structure of Formula V shown below and retains the structure disclosed in Table 5 by way of example and not limitation: Selected from the group of metazolamide carbonic anhydrase inhibitors. In addition, metazolamide carbonic anhydrase inhibitors useful in the practice of the methods of the invention are described in US Pat. No. 5,225,424, which is hereby incorporated by reference in its entirety. Incorporated.

In one embodiment, R ¹⁷ is C _1-8 and in another embodiment, R ¹⁷ is C _1-4 . In yet another embodiment, R ¹⁷ is methyl.

  In yet another embodiment, the carbonic anhydrase inhibitor is represented by the general structure of Formula VI shown below, and by way of example and not limitation, possesses the structure disclosed in Table 6: Selected from the group of thienothiazine sulfonamide carbonic anhydrase inhibitors. In addition, thienothiazine sulfonamide carbonic anhydrase inhibitors useful in the practice of the methods of the invention are described in US Pat. Nos. 5,344,929 and 5,424,448, both of which are All of which are incorporated herein by reference.

In the formula:
R ₁₈ and R ₁₉ are H or C _1-4 alkyl;
R ₂₀ is C _1-6 alkyl, CH ₂ (CH ₂ ) _n OR ₂₁ , where n is 1-4; and R ₂₁ is CH ₃ , n is 1-4 (CH _{2 N} CH ₃ or (CH ₂ ) _n Ar ₂ , wherein Ar ₂ is unsubstituted phenyl, 3-methoxyphenyl, or 4-methoxyphenyl, and n is 1 or 2.

  In a further embodiment, the carbonic anhydrase inhibitor is represented by the general structure of Formula VII shown below, and by way of example and not limitation, thienothia possessing the structure disclosed in Table 7: Selected from the group of ginsulfonamide carbonic anhydrase inhibitors. In addition, thienothiazine sulfonamide carbonic anhydrase inhibitors useful in the practice of the methods of the invention are described in US Pat. No. 5,464,831, which is incorporated herein by reference. Everything is incorporated.

In the formula:
R ₂₂ is C _1-6 , substituted with H, unsubstituted or optionally substituted with OH, C _1-4 alkoxy, NR ₂₄ R ₂₅ , OC (═O) R ₂₆ or C (═O) R _26. Is alkyl;
R ₂₃ is H; C _1-8 alkyl; OH, NR ₂₄ R ₂₅ , halogen, C _1-4 alkoxy, C _2-4 alkoxy, C _1-4 alkoxy, OC (═O) R ₂₆ , S (= O) _m R ₂₈ , or C _1-8 alkyl substituted with C (═O) R ₂₆ ; C unsubstituted or optionally substituted with OH, NR ₂₄ R ₂₅ , or C _1-4 alkoxy _3-7 alkenyl; C _3-7 alkynyl which is unsubstituted or optionally substituted with OH, NR ₂₄ R ₂₅ , or C _1-4 alkoxy; unsubstituted or optionally C _1-3 alkyl; C _{1-3 haloalkyl, OH, (CH 2) n} NR 24 R 25, _{halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, OC (= O) R 26} , C (= O) R 26, S = _O) a _{C 0-3} alkyl substituted with _{R 27,} which may be substituted with _{m R 28} or _SO 2 _NR 24 _{R 25,} m wherein is 0-2, and n is 0 2;
R ₂₄ and R ₂₅ are independently H; C _1-8 alkyl; C _2-4 alkyl optionally substituted with OH, halogen, C _1-4 alkoxy or C (═O) R ₂₆ ; OH; C _{1 -4} alkoxy; optionally OH, halogen, C _1-4 alkoxy or C _2-4 alkoxy substituted with C (═O) R ₂₆ ; or R ₂₄ and R ₂₅ are joined to form O, A ring of 5 or 6 atoms selected from S, C or N can be formed, which is unsubstituted or optionally OH at the carbon, (= O), halogen, C _{1- 4} alkoxy, C (═O) R ₂₆ , C _1-6 alkyl, optionally OH, halogen, C _1-4 alkoxy, C _1-6 alkyl substituted with C (═O) R ₂₆ , or at nitrogen C _1-4 alkoxy, C In _{= O) R 26, S (} = O) m R 28, C 1-6 alkyl or optionally OH, _{halogen, C 1-4} alkoxy, _C (= _O) C _2-6 alkyl substituted with _{R 26} Or can be substituted by (═O) _m in sulfur, where m is 0-2;
R _{26 is, C 1-8} alkyl; optionally _{OH, NR} 24 _{R 25, halogen, C 1-4} alkoxy or _C (= _O) C substituted with _{R 29 1-4 alkyl; C 1-4} alkoxy; Optionally OH, NR ₂₄ R ₂₅ , halogen or C _1-4 alkoxy substituted C _2-4 alkoxy; or NR ₂₄ R ₂₅ ;
R ₂₇ is from C, N, O or S such as benzene, furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine pyrimidine, pyridazine, and pyrazine. Is a monocyclic ring system of 5 or 6 atoms composed of;
R ₂₈ is C _1-4 alkyl; C _2-4 alkyl optionally substituted with OH, NR ₂₄ R ₂₅ , C _1-4 alkoxy or C (═O) R ₂₆ ; unsubstituted or optionally OH, (CH ₂ ) _n NR ₂₄ R ₂₅ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₂₆ , S (═O) _m C _1-4 alkyl or SO ₂ NR R ₂₇ which can be substituted with ₂₄ R ₂₅ ; where m is 0-2 and n is 0-2; and R ₂₉ is C _1-4 alkyl; C _1-4 Alkoxy; amino, C _1-3 alkylamino, di-C _1-3 alkylamino.

  In another embodiment, the carbonic anhydrase inhibitor is represented by the general structure of Formula VIII shown below, and by way of example and not limitation, thieno possessing the structure disclosed in Table 8: Selected from the group of thiazine sulfonamide carbonic anhydrase inhibitors. In addition, thienothiazine sulfonamide carbonic anhydrase inhibitors useful in the practice of the methods of the invention are described in US Pat. No. 5,510,347, which is hereby incorporated by reference. Everything is incorporated.

In the formula:
R ₃₀ is H or C _1-2 alkyl;
R ₃₁ is H; C _1-6 unsubstituted or optionally substituted with OH, C _1-4 alkoxy, NR ₃₄ R ₃₅ , OC (═O) R ₃₆ or C (═O) R ₃₆ Is alkyl;
R ₃₂ is H; C _1-6 alkyl; OH, NR ₃₄ R ₃₅ , halogen, C _1-4 alkoxy, C _2-4 alkoxy, C _1-4 alkoxy, OC (═O) R ₃₆ , S (= It is a _{C (= O) R 36;} O) m R 37 or _C (= _O) C _2-4 alkyl substituted with _{R 36,;}
R ₃₃ is H; C _1-8 alkyl; OH, NR ₃₄ R ₃₅ , halogen, C _1-4 alkoxy, C _2-4 alkoxy, C _1-4 alkoxy, OC (═O) R ₃₆ , S (= C) C _1-8 alkyl substituted with O) _m R ₃₇ , or C (═O) R ₃₆ ; C unsubstituted or optionally substituted with OH, NR ₃₄ R ₃₅ , or C _1-4 alkoxy _1-7 alkenyl; C _3-7 alkynyl which is unsubstituted or optionally substituted with OH, NR ₃₄ R ₃₅ , or C _1-4 alkoxy; unsubstituted or optionally C _1-3 alkyl; C _{1-3 haloalkyl, OH, (CH 2) n} NR 34 R 35, _{halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, OC (= O) R 36} , C (= O) R 36, S = _O) is _{m R 38} or _{C 1-3} alkyl substituted with _{R 37,} which may be substituted with _SO 2 _NR 34 _{R 35,} m wherein is 0-2, and n is 0 2;
R ₃₄ and R ₃₅ are H; C _1-8 alkyl; C _2-4 alkyl optionally substituted with OH, halogen, C _1-4 alkoxy or C (═O) R ₃₆ ; OH; C _1-4 Alkoxy; optionally OH, halogen, C _1-4 alkoxy or C _2-4 alkoxy substituted with C (═O) R ₃₆ ; or R ₃₄ and R ₃₅ are joined to form O, S, A ring of 5 or 6 atoms selected from C or N can be formed, which is unsubstituted or optionally OH, (═O), halogen, C _1-4 alkoxy at carbon _{, C (= O) R 36} , C 1-6 alkyl, optionally OH, _{halogen, C 1-4} alkoxy, C (= _O)) by _{C 1-6} alkyl substituted with _{R 36,} or a nitrogen C _1-4 alkoxy, C (= ) By _{R 36, S (= O)} m R 38, C 1-6 alkyl or optionally OH, _{halogen, C 1-4} alkoxy, with _C (= _O) C _2-6 alkyl substituted with _{R 36;} or May be substituted by (═O) _m in sulfur, where m is 0-2;
R _{36 is, C 1-8} alkyl; optionally _{OH, NR} 34 _{R 35, halogen, C 1-4} alkoxy or _C (= _O) C substituted with _{R 39 1-4 alkyl; C 1-4} alkoxy; C _2-4 alkoxy optionally substituted with OH, NR ₃₄ R ₃₅ , halogen or C _1-4 alkoxy; or NR ₃₄ R ₃₅ ;
R ₃₇ is from C, N, O or S such as benzene, furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine pyrimidine, pyridazine, and pyrazine. A composed 5 or 6 atom monocyclic ring system; wherein R ₃₇ is unsubstituted or optionally OH, (CH ₂ ) _n NR ₃₄ R ₃₅ , halogen, C _1-4 Can be substituted by alkoxy, C _1-4 haloalkoxy, C (═O) R ₃₆ , S (═O) _m C _1-4 alkyl or SO ₂ NR ₃₄ R ₃₅ ; 2 and n is 0-2;
R ₃₈ is C _1-4 alkyl; C _2-4 alkyl optionally substituted with OH, NR ₃₄ R ₃₅ , C _1-4 alkoxy or C (═O) R ₃₆ ; and R ₃₉ is C _1-4 alkyl; C _1-4 alkoxy; amino, C _1-3 alkylamino, di-C _1-3 alkylamino.

  In yet another embodiment, the carbonic anhydrase inhibitor is represented by the general structure of Formula VIIII shown below, and by way of example and not limitation, possesses the structure disclosed in Table 9: Selected from the group of sulfonamide carbonic anhydrase inhibitors. In addition, sulfonamide carbonic anhydrase inhibitors useful in the practice of the methods of the invention are described in US Pat. No. 5,538,966, which is hereby incorporated by reference in its entirety. Is done.

Wherein G ₂ , J and the two atoms of the thiophene ring to which they are connected are represented by the following formula:

Forming a 6-membered ring selected from:
In the formula:
Z ₄ is Z _4a , Z _4a is C _1-8 alkyl; C 1-3 alkyl-C 3-6 cycloalkyl; CH ₂ C (═O) R ₄₆ ; CH ₂ C (═O) R ₄₁ R ₄₂ ; CH ₂ CN; one or more hydroxyl, C _1-4 alkoxy, C _2-4 alkoxy-C _1-4 alkoxy, OC (═O) R ₄₀ , N (R ₄₁ ) C (═O) C _2-8 alkyl substituted with R ₄₀ , halogen, CN, NR ₄₁ R ₄₂ , SO _n R ₄₃ or C (═O) R ₄₄ , either of which is unsubstituted, or one or more Many C _1-4 alkyl, C _1-4 alkoxy, hydroxy, halogen, nitrile, NR ₄₁ R ₄₂ , SO _n R ₄₃ , C (═O) R ₄₄ or hydroxy, NR ₄₁ R ₄₂ , halogen, CO ₂ R ₄₀ Or C _1-3 C _1-4 alkyl substituted with an aromatic group selected from phenyl or Q can be substituted with C _1-4 alkyl substituted with alkoxy; unsubstituted or hydroxyl, C _{1-4 C 3-8} alkenyl substituted with alkoxy or _NR 41 _{R 42;} unsubstituted or _hydroxyl, be a _{C 1-4} alkoxy or _NR 41 _{C 3-8} alkynyl substituted with _{R 41;} and When Z ₄ is Z _4b , Z _4b is either unsubstituted or one or more C _1-4 alkyl, C _1-4 alkoxy, hydroxy halogen, nitrile, NR ₄₁ R ₄₂ , SO _n R ₄₃ , C (═O) R ₄₄ , or substituted with hydroxy, NR ₄₁ R ₄₂ , halogen or C _1-3 alkoxy An aromatic group selected from phenyl or Q, which can be substituted with substituted C _1-4 alkyl;
Y ₂ is hydrogen; C _1-8 alkyl; one or more hydroxyl, C _1-4 alkoxy, C _2-4 alkoxy-C _1-4 alkoxy, OC (═O) R ₄₀ , N (R ₄₁ ) C (= O) R ₄₀ , halogen, CN, NR ₄₁ R ₄₂ , SO _n R ₄₃ , or C _1-6 alkyl substituted with C (═O); either of them is unsubstituted or one One or more C _1-4 alkyl, C _1-4 alkoxy, hydroxy, halogen, nitrile, NR ₄₁ R ₄₂ , SO _n R ₄₃ , C (═O) R ₄₄ , or hydroxy, NR ₄₁ R ₄₂ , halogen , _CO 2 _{R 40} or _{C 1-3 C 1-4} Al substituted with an aromatic group selected from phenyl or Q can be substituted with _{C 1-4} alkyl substituted with alkoxy Le; unsubstituted or _hydroxyl, been _{C 3-8} alkenyl substituted by _{C 1-4} alkoxy or _NR 41 _{R 42;} substituent which is not substituted, or _hydroxyl, by _{C 1-4} alkoxy or _NR 41 _{R 42} C _3-8 alkynyl;
R _{40 is, C 1-6} alkyl; hydroxy, _{halogen, C 1-4 alkoxy, NR} 41 _{R 42} or C (= _O) has been _{C 1-6} alkyl substituted with _{R 44;} not substituted, or one Or more phenyl, which can be substituted with C _1-4 alkyl, alkoxy, hydroxy or halogen;
R ₄₁ and R ₄₂ are hydrogen; C _1-4 alkyl; CH ₂ CN; C _1-3 alkyl-C _3-6 cycloalkyl; C _3-8 cycloalkyl; hydroxyl, halogen, CN, C _1-4 alkoxy Or C _2-4 alkyl substituted with C (═O) R ₄₄ ; hydroxyl; C _1-4 alkoxy; C _2-4 alkoxy substituted with hydroxyl, NR ₄₁ R ₄₂ , halogen or C _1-4 alkoxy; C _3-8 alkenyl which is unsubstituted or substituted by hydroxy or C _1-4 alkoxy; independently from C _3-8 alkynyl which is unsubstituted or substituted by hydroxyl or C _1-4 alkoxy or it is selected; or more R ₄₁ and R _42, together with the nitrogen atom to which they are attached, pyrrolidine, oxazolidine, Ruphorin, thiomorpholine, thiomorpholine 1,1-dioxide, piperazine, 2-oxa-5-azabicyclo [2.2.1] heptane, 2-oxa-5-azabicyclo [3.2.1] octane, thiazolidine, or Can be incorporated into a saturated heterocyclic ring of 5 to 8 atoms, which can contain a second heteroatom selected from O, S or N, such as thiazolidine 1,1-dioxide, Is unsubstituted or hydroxyl in carbon, (═O), halogen, C _1-4 alkoxy, C (═O) R ₄₄ , C _1-4 alkyl, hydroxyl, halogen, C _1-4 alkoxy, C (= O) by _{C 1-4} alkyl substituted with _{R 5,} or _{C 1-4} alkoxy in _{nitrogen, C (= O) R 44} , SO n R 43, C 1- Alkyl or may be hydroxyl, _halogen, by _{C 1-4} alkoxy or C (= _{O) C 1-4} alkyl substituted with _{R 44;}
R ₄₃ is C _1-4 alkyl; C _2-4 alkyl substituted with hydroxyl, halogen, NR ₄₁ R ₄₂ or C _1-3 alkoxy;
R _{44 is, C 1-6} alkyl; hydroxy, _halogen, SO _n R _{43, C 1-4 alkoxy, C} substituted with _NR 41 _{R 42} or C (= _{O) R 45 1-6} alkyl; either of Is unsubstituted or one or more C _1-4 alkyl, C _1-4 alkoxy, hydroxy, halogen, nitrile, NR ₄₁ R ₄₂ , SO _n R ₄₃ or C (═O) R ₄₄ , or _{hydroxy, NR} 41 _{R 42,} halogen, or _{C 1-3 C 1-4} substituted with an aromatic group selected from phenyl or Q can be substituted with _{C 1-4} alkyl substituted with alkoxy Alkyl; hydroxyl; C _1-4 alkoxy; C _2-4 alkoxy substituted with hydroxyl, NR ₄₁ R ₄₂ , halogen or C _1-4 alkoxy NR ₄₁ R ₄₂ ;
R ₄₅ is C _1-4 alkyl; C _1-4 alkoxy; amino; C _1-3 alkylamino; (C _1-3 alkyl) 2 amino;
R ₄₆ is _hydroxyl, be a _{C 1-4} alkoxy, _{hydroxyl, NR} 41 _{R 42} or _{C 1-4 C 1-4} alkoxy substituted with alkoxy;
n is 0, 1, or 2; and Q is thiophene, furan, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine, pyrimidine, pyridazine, and pyrazine. Is a monocyclic 5 or 6 membered heterocyclic ring system in which one or more heteroatoms, nitrogen, oxygen and / or sulfur are incorporated into the ring.

  In yet another embodiment, the carbonic anhydrase inhibitor is represented by the general structure of Formula X shown below and, by way of example and not limitation, possesses the structure disclosed in Table 10: Selected from the group of thiophenesulfonamide carbonic anhydrase inhibitors. In addition, thiophenesulfonamide carbonic anhydrase inhibitors useful in the practice of the methods of the invention are described in US Pat. No. 5,646,142, which is hereby incorporated by reference in its entirety. Incorporated.

In the formula:
R ₄₇ is, H; _{OH; C 1-6} alkoxy; unsubstituted or optionally _{OH, NR 49 R 50, OC} (= O) R 51 or _C (= _O) C ₁ substituted with _{R 51 -6 alkyl; NR 49 R 50; OC (} = O) R 51; C (= O) R 51; optionally _{OH, NR} 49 _{R 50, halogen, C 1-4} alkoxy or C (= _{O) R 51} Substituted C _2-4 alkoxy; any of these are unsubstituted or optionally OH, (CH ₂ ) _n NR ₄₉ R ₅₀ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (= O) R ₅₁ , S (= O) _m R ₅₃ or SO ₂ NR ₄₉ R ₅₀ is phenyl or R ₅₂ ; where _m is 0-2 and n Is 0-2 There _{proviso, R 47} is OH, _{alkoxy, NR} 49 _{R 50,} or OC (= _{O) R 51,} if this is connected to the 4-position, and _{R 47} is _{R 52,} and 3-position connection The R ₅₂ rings are connected by a carbon-carbon single bond;
R _{48 is, S (= O) m C} 2-8 alkyl substituted with _{R 53;} a S ₍₌ O) _{C 4-7} alkenyl substituted with _{m R 53,} wherein m is 2-0 Yes;
R ₄₉ and R ₅₀ are H; C _1-8 alkyl; C _2-4 alkyl optionally substituted with OH, halogen, C _1-4 alkoxy or C (═O) R ₅₁ ; C _1-4 alkoxy; Is C _2-4 alkoxy optionally substituted with OH, halogen, C _1-4 alkoxy, or C (═O) R ₅₁ ; or R ₄₉ and R ₅₀ are joined to form O, S, C Or a ring of 5 or 6 atoms selected from N, which may be unsubstituted or optionally substituted at the carbon with OH, (═O), halogen, C _1-4 alkoxy, _{C (= O) R 51,} C 1-6 alkyl, optionally OH, _{halogen, C 1-4} alkoxy, with _C (= _O) C _1-6 alkyl substituted with _{R 51,} or a nitrogen _{C 1- 4} alkoxy, C (= O) R _{1, S (= O) m} R 53, C 1-6 alkyl or optionally OH, _{halogen, C 1-4} alkoxy, with _C (= _O) C _2-6 alkyl substituted with _{R 51,} or in sulfur (= _O) it can be substituted by _m, m wherein is 0-2;
R _{51 is, C 1-8} alkyl; optionally _{OH, NR} 49 _{R 50, halogen, C 1-4} alkoxy or _C (= _O) C substituted with _{R 54 1-8 alkyl; C 1-4} alkoxy; C _2-4 alkoxy optionally substituted with OH, NR ₄₉ R ₅₀ , halogen or C _1-4 alkoxy; or NR ₄₉ R ₅₀ ;
R ₅₂ is composed of C, N, O or S such as furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine pyrimidine, pyridazine, and pyrazine. A monocyclic ring system of 5 or 6 atoms;
R ₅₃ is C _1-4 alkyl; C _3-5 alkenyl, optionally C _2-4 alkyl substituted with OH, NR ₄₉ R ₅₀ , C _1-4 alkoxy or C (═O) R ₅₁ ; Either is unsubstituted or optionally OH, (CH ₂ ) _n NR ₄₉ R ₅₀ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₅₁ , S (= O) _m C _1-4 alkyl or SO ₂ NR ₄₉ R ₅₀ can be substituted with phenyl or R ₅₂ ;
m is 0-2 and n is 0-2; and R ₅₄ is C _1-4 alkyl; C _1-4 alkoxy; amino, C _1-3 alkylamino, or di-C _1-3 Alkylamino.

  In yet another embodiment, the carbonic anhydrase inhibitor is represented by the general structure of Formula XI shown below, and by way of example and not limitation, possesses the structure disclosed in Table 11: Selected from the group of sulfonamide carbonic anhydrase inhibitors. In addition, sulfonamide carbonic anhydrase inhibitors useful in the practice of the methods of the invention are described in US Pat. Nos. 5,932,572 and 5,679,670, both of which are described herein. All of which are incorporated herein by reference.

In the formula: W and Y ₃ are listed in Table A.

  In a further embodiment, the carbonic anhydrase inhibitor is represented by the general structure of Formula XII shown below, and by way of example and not limitation, sulfonamides possessing the structure disclosed in Table 12: Selected from the group of carbonic anhydrase inhibitors. In addition, sulfonamide carbonic anhydrase inhibitors useful in the practice of the method of the invention are described in US Pat. Nos. 6,248,735, 6,264,935 and 6,316,443, which All of which are incorporated herein by reference in their entirety.

In the formula:
A ₄ is carbon or nitrogen;
Z ₅ is NHR ₆₅ or OR ⁶⁵ ;
R ⁶⁵ is either straight or branched C _1-6 alkyl;
R ⁶⁶ is hydrogen, C _1-3 alkyl, or C _1-4 alkoxy-C _1-4 alkyl; and X ₃ is S (O) ₂ or C (O) ₂ .

  In another embodiment, the carbonic anhydrase inhibitor is represented by the general structure of Formulas XIIIa, XIIIb, XIIIc, and XIIId shown below and disclosed by way of example and not limitation: Selected from the group of sulfonamide carbonic anhydrase inhibitors possessing the structure In addition, sulfonamide carbonic anhydrase inhibitors useful in the practice of the methods of the invention are described in US Pat. No. 6,313,155, which is hereby incorporated by reference in its entirety. Is done.

Where A ₅ together with the two carbon atoms marked α and β is the following formula:

The basis of
In the formula:
X ₄ is S, SO, SO ₂ or CH ₂ ;
Y ₄ is S, O, or NR ³ where R ³ is hydrogen, C _1-3 alkyl, or benzyl;
n is 1 or 2;
R ⁶⁷ , R ⁶⁸ , R ⁶⁹ , R ⁷⁰ are independently:
(1) hydrogen,
(2) OR ⁷¹ , where R ⁷¹ is:
(A) hydrogen,
(B) C _1-5 alkyl, either unsubstituted or substituted with OH, or wherein R ⁷² and R ⁷³ are independently hydrogen or C _1-5 alkyl, or Join with the nitrogen to which they are attached to form a heterocyclic ring such as piperidino, morpholino, or piperazino;
(C) C _1-5 alkanoyl which is either unsubstituted or substituted with OH, NR ⁷² R ⁷³ , NHCOR ⁷⁴ or COR ⁷⁴ , wherein R ⁷⁴ is OH, NR ⁷² R ⁷³ or C _1-5 alkoxy;
(D) COR ⁷⁵ , wherein R ⁷⁵ is NR ⁷² R ⁷³ or a 5- or 6-membered aromatic heterocycle such as pyridyl, imidazolyl, pyrazinyl, thiazolyl, thienyl, or oxazolyl;
(3) NR ₇₃ ;
(4) NHR ⁷⁶ , where R ⁷⁶ is:
(A) SO ₂ NR ⁷² R ⁷³ ,
(B) SO ₂ R ⁷⁷ , wherein R ⁷⁷ is C _1-5 alkyl, or (c) CONR ⁷² R ⁷³ ;
(5) Not substituted or:
(A) OR ⁷¹ ,
(B) CN,
(C) NR ⁷² R ⁷³ , or (d) COR ⁷⁴
Any C _1-5 alkyl substituted with:
(6) SO ₂ R ⁷⁷ ,
^{_{(7) SO 2 NR 72 R}} 73, or (8), such as chloro, bromo or fluoro - halo,
Is selected from;
(9) R ⁶⁷ and R ⁶⁹ , or R ⁶⁸ and R ⁷⁰ are selected together to represent a double bond;
(10) R ⁶⁷ and R ⁶⁸ , or R ⁶⁹ and R ⁷⁰ are selected together;
(A) = O, or (b) = NOR ⁷⁸ , wherein R ⁷⁸ is hydrogen or C _1-3 alkyl; and one of the CH ₂ groups of (CH ₂ ) _n is COR ⁷⁴ , It can be substituted with CH ₂ R ⁷⁴ or CH ₂ COR ⁷⁴ .

  In yet another embodiment, the carbonic anhydrase inhibitor is selected from the group of sulfonamide carbonic anhydrase inhibitors represented by the general structure of XIIIb.

  Where

And
In the formula:
X ₅ is S, SO ₂ or CH ₂ ;
Y ₅ is S, O, or NR ⁸⁵ , wherein R ⁸⁵ is H, C _1-3 alkyl or benzyl,
m is 0 or 1,
R ⁷⁹ is
(1) hydrogen,
(2) unsubstituted or one or more (a) hydroxy,
(B) C _1-3 alkoxy,
(C) R ⁸³ R ⁸⁴ NC _1-5 alkyl, wherein R ⁸³ and R ⁸⁴ are:
(I) hydrogen and (ii) independently selected from C _1-5 alkyl, or selected together with the nitrogen to which they are attached, to form a heterocyclic ring such as morpholine, piperidine, pyrilodine, or piperazine Form,
Any phenyl, which is substituted with
(3) OH,
(4) = O; or (5) NR ⁸³ R ⁸⁴ ,
R ⁸⁰ is
(1) hydrogen,
(2) CN,
(3) Phenyl- _C1-3alkyl , wherein phenyl is unsubstituted or one or more (a) hydroxy,
Either (b) C _1-3 alkoxy, or (c) substituted with R ⁸³ R ⁸⁴ NC _1-5 alkyl;
Is;
R ⁸¹ is
(1) hydrogen,
(2) C _1-5 alkyl,
(3) Phenyl-C _1-3 alkyl, wherein phenyl is substituted or one or more:
(A) hydroxy,
Either (b) C _1-3 alkoxy, or (c) substituted with R ⁸³ R ⁸⁴ NC _1-3 alkyl,
(4) Not substituted or one or more:
(A) hydroxy,
(B) C _1-3 alkoxy, or (c) R ⁸³ R ⁸⁴ NC _1-3 alkyl, or (d) any phenyl substituted with halo, such as chloro or fluoro,
(5) 5- or 6-membered aromatic heterocycle, such as furyl, pyridyl, or thienyl, which are either unsubstituted or substituted with R ⁸³ R ⁸⁴ NC _1-3 alkyl,
(6) NR ⁸³ R ⁸⁴ , and (7) C _2-5 alkyl substituted with NR ⁸³ R ⁸⁴ ;
R ⁸² is
(1) hydrogen,
(2) C _1-3 alkyl, or (3) C _1-3 alkenyl such as methylene;
Provided that when R ⁷⁹ is other than phenyl or substituted phenyl and R ⁸⁰ is hydrogen, one of R ⁸¹ and R ⁸² is other than hydrogen.

  In a further embodiment, the carbonic anhydrase inhibitor is selected from the group of sulfonamide carbonic anhydrase inhibitors represented by the general structure of XIIIc.

In the formula:
R ⁸⁶ is
(1) H,
(2) C _1-4 alkyl, or (3)
(A) OH,
(B) halogen,
(C) C _1-4 alkoxy or (d) C (═O) R ⁹²
C _2-4 alkyl substituted with
R ⁸⁷ is
(1) H,
(2) C _1-8 alkyl;
(3)
(A) OH,
(B) NR ⁹⁰ R ⁹¹ ,
(C) halogen,
(D) C _1-4 alkoxy, or (e) C (═O) R ⁹²
C _2-8 alkyl substituted with
(4) not substituted or (a) OH,
(B) NR ⁹⁰ R ⁹¹ , or (c) C _3-7 alkenyl substituted with C _1-4 alkoxy,
(5) not substituted or (a) OH,
(B) NR ⁹⁰ R ⁹¹ , or (c) C _3-7 alkynyl substituted with C _1-4 alkoxy,
(6)
(A) phenyl, or (b) unsubstituted, or (i) OH,
(Ii) (CH ₂ ), NR ⁹⁰ R ⁹¹ ,
(Iii) halogen,
(Iv) C _1-4 alkoxy,
(V) C _1-4 haloalkoxy,
(Vi) C (= O) R ⁹² ,
(Vii) S (= O) _m R ⁹³ , or (viii) SO ₂ NR ⁹⁰ R ⁹¹
Heteroaryl substituted with
Where m is 0-2 and n is 0-2;
C _1-3 alkyl substituted with
(7)
(A) NR ⁹⁰ R ⁹¹ ,
(B) halogen,
(C) C _1-4 alkoxy, or (d) C (═O) R ⁹²
C _2-4 alkoxy substituted with
(8) phenyl, or (9) unsubstituted, or (a) OH,
^{_{(B) (CH 2) n}} NR 90 R 91,
(C) halogen,
(D) C _1-4 alkoxy,
(E) C _1-4 haloalkoxy,
(F) C (= O) R ⁹² ,
(G) S (= O) _m R ⁹³ , or (h) SO ₂ NR ⁹⁰ R ⁹¹
Heteroaryl substituted with
And
Where m is 0-2 and n is 0-2;
Provided that both R ⁸⁶ and R ⁸⁷ cannot be H, or R ⁸⁶ and R ⁸⁷ are saturated with 5 or 6 atoms selected from O, S, C, or N. A ring can be formed, said ring being unsubstituted or in C (1) OH,
(2) NR ⁹⁰ R ⁹¹ ,
(3) halogen,
(4) C _1-4 alkoxy,
(5) C (= O) R ⁹² ,
(6) C _1-6 alkyl,
(7)
(A) OH,
(B) NR ⁹⁰ R ⁹¹ ,
(C) halogen,
(D) C _1-4 alkoxy,
(E) C (= O) R ⁹²
Substituted with C _1-6 alkyl substituted with or in N (1) NR ⁹⁰ R ⁹¹ ,
(2) C _1-4 alkoxy,
(3) C (O) R ⁹² ,
(4) C _1-6 alkyl,
(5)
(A) OH,
(B) NR ⁹⁰ R ⁹¹ ,
(C) halogen,
(D) C _1-4 alkoxy, or (e) C (═O) R ⁹²
Substituted with C _1-6 alkyl substituted with
R ⁸⁸ is
(1) H,
(2) halogen,
(3) C _1-4 alkyl,
(4) C _1-8 alkoxy,
(5) C _1-8 alkylthio,
(6)
(A) OH,
(B) NR ⁹⁰ R ⁹¹ ,
(C) halogen,
(D) C _1-4 alkoxy,
(E) C (= O) R ⁹²
C _2-8 alkoxy substituted with
(7) C _1-4 alkyl substituted with R ⁸⁹ ,
Is;
(8) R ⁸⁶ and R ⁸⁷ form a 5- to 7-membered ring, said ring being unsubstituted or substituted with R ⁸⁹ ;
R ⁸⁹ is
(1) OH,
(2) not substituted or (a) OH,
(B) NR ⁹⁰ R ⁹¹ ,
(C) halogen,
(D) C _1-4 alkoxy, or (e) C (═O) R ⁹²
C _1-4 alkyl substituted with
(3) C _1-4 alkoxy,
(4)
(A) OH,
(B) NR ⁹⁰ R ⁹¹ ,
(C) halogen,
(D) C _1-4 alkoxy, or (e) C (═O) R ⁹²
C _2-4 alkoxy substituted with
(5) NR ⁹⁰ R ⁹¹ ,
(6) phenyl, or (7) unsubstituted or (a) OH,
^{_{(B) (CH 2) n}} NR 90 R 91,
(C) halogen,
(D) C _1-4 alkoxy,
(E) C _1-4 haloalkoxy,
(F) C (= O) R ⁹² ,
(G) S (= O) _m R ⁹³ , or (h) SO ₂ NR ⁹⁰ R ⁹¹
A heteroaryl substituted with
Where m is 0-2 and n is 0-2;
Provided that when R ⁸⁸ is in position 4 and is H or halogen, R ⁸⁶ and R ⁸⁷ are
(1) H,
(2)
(A) OH,
(B) C _1-6 alkoxy,
(C) provided that it is not C _1-6 alkoxy substituted with C _2-6 alkoxycarbonyl; or (3) saturation consisting of atoms selected from C, O, S, N joined together Or an unsaturated 5, 6 or 7 membered ring, where N, when saturated, is substituted with H or C _1-6 alkyl, wherein C is C _1-6 alkyl, C Substituted with _1-6 alkoxy or OH;
And when R ⁸⁸ is in the 5-position and is H, Cl, Br or C _1-3 alkyl, R ⁸⁶ and R ⁸⁷ are not H or C _1-4 alkyl;
R ⁹⁰ and R ⁹¹ are the same or different and (1) H,
(2) C _1-4 alkyl,
(3)
(A) OH,
(B) halogen,
(C) C _1-4 alkoxy, or (d) C (═O) R ⁹²
C _2-4 alkyl substituted with
(4) C _1-4 alkoxy,
(5)
(A) OH,
(B) halogen,
(C) C _1-4 alkoxy, or (d) C (═O) R ⁹²
C _2-4 alkoxy substituted with
(6) not substituted, or (a) OH,
(B) NR ⁹⁰ R ⁹¹ , or (c) C _3-7 alkenyl substituted with C _1-4 alkoxy,
(7) not substituted, or (a) OH,
(B) NR ⁹⁰ R ⁹¹ , or (c) C _3-7 alkynyl substituted with C _1-4 alkoxy,
(8) C _1-2 alkyl C _3-5 cycloalkyl, or (9) R ⁹⁰ and R ⁹¹ represent a ring of 5 or 6 atoms selected from O, S, C, and N. And said ring is unsubstituted or in C (a) OH,
(B) (= O),
(C) halogen,
(D) C _1-4 alkoxy,
(E) C (= O) R ⁹² ,
(F) C _1-6 alkyl,
(G)
(I) OH,
(Ii) halogen,
(Iii) C _1-4 alkoxy,
(Iv) C (= O) R ⁹²
C _1-6 alkyl substituted with
Or in N (a) C _1-4 alkoxy,
(B) C (= O) R ⁹² ,
(C) S (= O) _m R ⁹³ ,
(D) C _1-6 alkyl, or (e)
(I) OH,
(Ii) halogen,
(Iii) C _1-4 alkoxy,
(Iv) C (= O) R ⁹²
C _2-6 alkyl substituted with
Or substituted in (= O) _m in S, where m is 0-2;
R ⁹² is
(1) C _1-8 alkyl,
(2)
(A) OH,
(B) NR ⁹⁰ R ⁹¹ ,
(C) halogen,
(D) C _1-4 alkoxy, or (e) C (═O) R ⁹⁴
C _1-8 alkyl substituted with
(3) C _1-4 alkoxy,
(4)
(A) OH,
(B) NR ⁹⁰ R ⁹¹ ,
(C) halogen, or (d) C _1-4 alkoxy
C _2-4 alkoxy substituted with or (5) NR ⁹⁰ R ⁹¹
Is;
R ⁹³ is
(1) C _1-4 alkyl,
(2)
(A) OH,
(B) NR ⁹⁰ R ⁹¹ ,
(C) halogen,
(D) C _1-4 alkoxy, or (e) C (═O) R ⁹²
C _2-4 alkyl substituted with
R ⁹⁴ is
(1) C _1-4 alkyl,
(2) C _1-4 alkoxy,
(3) amino,
(4) C _1-3 alkylamino or (5) di-C _1-3 alkylamino; and G ₄ is C (═O) or SO ₂ .

  In still further embodiments, the carbonic anhydrase inhibitor is selected from the group of sulfonamide carbonic anhydrase inhibitors represented by the general structure of XIIId.

Wherein R ₉₅ is
(1) C _1-18 alkyl,
(2) C _3-6 cycloalkyl,
(3) C _3-6 cycloalkyl C _1-18 alkyl,
(4) C _1-18 alkyl C _3-6 cycloalkyl,
(5) haloalkyl,
(6) unsubstituted or (a) linear or branched C _1-10 alkyl (b) halo selected from bromo, chloro and fluoro, or (c) alkoxy selected from methoxy and ethoxy Aryl substituted with
(7) arylalkyl, wherein alkyl is C _1-4 and aryl is unsubstituted or substituted with fluoro, chloro, bromo or C _1-3 alkyl,
(8) C _2-18 hydroxyalkyl,
(9) C _2-18 aminoalkyl,
(10) C _2-6 alkenyl,
(11) C _2-6 alkynyl, or (12) aryl C _2-6 alkenyl.

  The carbonic anhydrase inhibitors used in the present invention can exist in tautomeric, geometric or stereoisomeric forms. Generally speaking, suitable carbonic anhydrase inhibitors that are in tautomeric, geometric or stereoisomeric forms have carbonic anhydrase activity of about 25% when present at a concentration of 100 μM or less. More typically about 50%, and even more typically compounds that inhibit about 75% or more. The present invention relates to cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereoisomers, d-isomers, l-isomers, and racemic mixtures thereof. And all such compounds including these and other mixtures thereof are contemplated. Such tautomeric, geometric or stereoisomeric forms of pharmaceutically acceptable salts are further included in the present invention. As used herein, the terms “cis” and “trans” refer to two carbon atoms connected by a double bond, each hydrogen atom on the same side of the double bond (“cis”), Or it refers to a form of geometric isomerism that is on the opposite side ("trans") of a double bond. Some of the compounds described contain alkenyl groups and are meant to include both cis and trans or “E” and “Z” geometric forms. Further, some of the compounds described contain one or more stereocenters and include, for each existing stereocenter, R, S, and mixtures or R and S forms. means.

Generally speaking, the pharmacokinetics of the particular drug being administered will specify the most preferred method of administration and administration. The carbonic anhydrase inhibitor can be administered as a pharmaceutical composition with or without a carrier. The term “pharmaceutically acceptable carrier” or “carrier” refers to any generally acceptable excipient or drug release composition that is relatively inert and non-toxic. Exemplary carriers are sterile water, salt solutions (such as Ringer's solution), alcohol, gelatin, talc, viscous paraffin, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, calcium carbonate, carbohydrates (eg, lactose, sucrose, dextrose) , Mannose, albumin, starch, cellulose) silica gel, polyethylene glycol (PEG), dry skim milk powder, rice flour, magnesium stearate, and the like. Suitable formulations and additional carriers ^{are, Remington's Pharmaceutical Sciences, (17} th Ed., Mack Pub.Co., Easton, Pa.) Are described in. Such formulations are sterilized and, if desired, auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers that do not react adversely with the active compound. It can be mixed with liquids, colorants, preservatives and / or aromatic substances. Typical preservatives can include potassium sorbate, sodium metabisulfite, methyl paraben, propyl paraben, thimerosal, and the like. The composition can further be combined with other active agents, such as enzyme inhibitors, if desired, to reduce metabolic degradation.

  Further, the carbonic anhydrase inhibitor can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The method of administration can specify how the composition is to be formulated. For example, the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulations can include standard carriers such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, or magnesium carbonate.

  In another embodiment, the carbonic anhydrase inhibitor is administered intravenously, parenterally, intramuscularly, subcutaneously, orally, nasally, topically, by inhalation, implantation, injection or by suppository. can do. Particularly suitable for intestinal or mucosal applications (including intraoral and nasal mucosa) are tablets, liquids, drops, suppositories or capsules. Syrups, elixirs and the like can be used when a sweetened vehicle is used. Liposomes, microspheres, and microcapsules are available and can be used. Pulmonary administration can be accomplished using any of a variety of release devices known in the art, such as an inhaler. For example, S.M. P. Newman (1984) in Aerosols and Lung, Clark and Davis (eds.), Butterworths, London, England, pp. 197-224; PCT application publication WO 92/16192; PCT application publication WO 91/08760. Particularly suitable for parenteral application are sterile solutions for injection, preferably oily or aqueous solutions, as well as implants containing suspensions, emulsions or suppositories. In particular, carriers for parenteral administration include dextrose in water, saline, pure water, ethanol, glycerin, propylene glycol, peanut oil, sesame oil, polyoxyethylene-polyoxypropylene block copolymers, and the like.

  The actual effective amount of the compound or drug can and will vary depending on the particular composition used, the mode of administration, and the age, weight and condition of the patient. The dosage for a particular individual patient can be determined by one skilled in the art using routine considerations. Generally, however, the amount of carbonic anhydrase inhibitor will be between about 0.5 and about 2000 milligrams per day, and more typically between about 100 and about 1000 milligrams per day. is there. The daily dose can be administered 1 to 4 times per day.

  By way of example, in one embodiment, when the carbonic anhydrase inhibitor is orally administered acetazolamide, the daily dose is typically about 250 per day administered in 1 to 4 doses per day. Or about 1000 milligrams. In another embodiment, when the carbonic anhydrase inhibitor is acetazolamide administered as an injection, the daily dose is typically about 100 to 500 milligrams per day, but this is 1 or 2 times per day Is administered.

  As a further example, in another embodiment, when the carbonic anhydrase inhibitor is orally administered diclofenamide, the daily dose is typically about 1 to 3 doses administered per day. 25 to about 200 milligrams.

  As yet a further example, in another embodiment, when the carbonic anhydrase inhibitor is orally administered methazolamide, the daily dose is typically administered from 1 to 3 doses per day. About 75 to about 300 milligrams.

  In general, the timing of administration of the cyclooxygenase-2 selective inhibitor relative to the administration of the carbonic anhydrase inhibitor can also vary from patient to patient. In one embodiment, the cyclooxygenase-2 selective inhibitor and the carbonic anhydrase inhibitor can be administered substantially simultaneously, meaning that the two agents can be administered to the patient at approximately the same time. For example, the cyclooxygenase-2 selective inhibitor is administered for a continuous period beginning on the same day of initiation of the carbonic anhydrase inhibitor and extending to a period after termination of the carbonic anhydrase inhibitor. Alternatively, the cyclooxygenase-2 selective inhibitor and the carbonic anhydrase inhibitor can be administered sequentially, meaning that they are administered at separate times during separate treatments. In one embodiment, for example, the cyclooxygenase-2 selective inhibitor is administered for consecutive periods beginning before administration of the carbonic anhydrase inhibitor and ending after administration of the carbonic anhydrase inhibitor. Of course, it is further possible that the cyclooxygenase-2 selective inhibitor can be administered either more frequently or less frequently than the carbonic anhydrase inhibitor. Furthermore, it will be apparent to those skilled in the art that various times and methods of administration can be combined and perhaps preferred in the practice of the present invention.

Indications Treated Generally speaking, a composition comprising a therapeutically effective amount of a cyclooxygenase-2 selective inhibitor and a therapeutically effective amount of a carbonic anhydrase inhibitor is It can be used to treat any type of patient's malignancy or disease associated with malignancy regardless of stage.

  In certain aspects, the composition prevents the development of all clinically manifest malignancies in a patient at risk of developing a malignant tumor, or pre-clinically manifests the development of a malignant tumor. Can be administered for either prevention. In other aspects, the composition can be administered to prevent the initiation of malignant tumor cells or to inhibit or reverse the progression of pre-malignant tumor cells to malignant cells. In yet other aspects, the composition can be administered to inhibit the growth, expansion or metastasis of malignant tumors, as well as for partial or total destruction of malignant tumor cells.

  The composition can be effectively used to treat many different types of malignant tumors. In one embodiment, the malignant tumor is an epithelial cell-derived malignant tumor (epithelial carcinoma). By way of example, epithelial malignant tumors include basal cell tumors, squamous cell carcinomas or adenocarcinomas. In another embodiment, the malignant tumor is gastrointestinal cancer. Gastrointestinal cancer includes lip cancer, oral cancer, esophageal cancer, small intestine cancer, gastric cancer and colon cancer. In yet another embodiment, the malignant tumor is liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer and skin cancer such as squamous cell and basal cell cancer, prostate cancer, brain cancer and kidney cell. Includes cancer types. The composition can also be used to treat fibrosis that often occurs with radiation therapy. In yet another embodiment, the composition can be used to treat patients with adenomatous polyps, including familial adenomatous polyposis (FAP).

  The cyclooxygenase-2 selective inhibitor and carbonic anhydrase inhibitor are administered in conjunction with any other drug or agent known in the art that further has use for treating or preventing malignant neoplastic disease or related diseases You can also In one embodiment, the antineoplastic agent comprises a folic acid antagonist (eg, methotrexate), a pyrimidine antagonist (eg, cytarabine, furoxyuridine, fludarabine, fluorouracil, and gemcitabine), a purine antagonist (eg, cladribine, mercaptopurine, thioguanine), and adenosine deaminase inhibition An antimetabolite comprising an agent (eg, pentostatin). In another embodiment, the antineoplastic agent is an alkylating agent such as chlorambucil, cyclophosphamide, busulfan, ifosfamide, melphalan, and thiotepa. In yet another embodiment, the antineoplastic agent is an akilator agent such as cisplatin, carboplatin, procarbazine, dacarbazine, and altretamine. In yet another embodiment, the antineoplastic agent is an antitumor antibiotic such as bleomycin, dactinomycin, and mitomycin. In still further embodiments, the antineoplastic agent is an immunological agent such as interferon. In another embodiment, the antineoplastic agent is a vinca alkaloid (eg, vinblastine vincristine and vinorelbine), epipodophyllotoxin (eg, etoposide and teniposide), taxane (eg, docetaxel and paclitaxel), and camptothecin (eg, topotecan) And irinotecan). Of course, those skilled in the art will recognize that the particular antineoplastic agent administered with the composition of the present invention will vary considerably depending on the type of malignant neoplastic disease being treated and the stage of its progression. .

Example 1-Determination of whether a composition reduces tumor cell growth The ability of a composition of the invention to reduce tumor cell growth can be readily determined. As used in the examples, "composition" must include any composition comprising a cyclooxygenase-2 selective inhibitor and a carbonic anhydrase inhibitor as detailed in the present invention. . By way of example, the cyclooxygenase-2 selective inhibitor used to test the composition can be celecoxib, rofecoxib, valdecoxib, etoroxib, parecoxib, or deracoxib. The carbonic anhydrase inhibitor can include acetazolamide, metazolamide, dorzolamide, or brinzolamide. In addition, various cell lines can be used to determine whether the composition reduces tumor cell growth. For example, these cell lines are: SW-480 (colon adenocarcinoma); HT-29 (colon adenocarcinoma), A-427 (lung adenocarcinoma); MCF-7 (breast adenocarcinoma); UACC-375 (melanoma) ); And DU-145 (prostate carcinoma). Cytotoxicity data obtained using these cell lines shows an inhibitory effect on malignant destruction. These cell lines are well characterized and are being used in the screening program for new anticancer drugs by the National Cancer Institute.

By way of example, the ability of a composition to inhibit tumor cell growth can be measured using the HT-29 human colon cancer cell line obtained from ATCC and the SRB assay. HT-29 cells have been previously characterized as an associated colorectal tumor cell culture model and are probably (Fog, J., and Trempe, G. In: Human Tumor Cells in Vitro, J. Fogh (eds.), Plenum Press, New York, pp. 115-159, 1975). In this assay, HT-29 cells were RPMI medium supplemented with 5% fetal bovine serum (Gemini Bioproducts, Inc., Carlsbad, Calif.) And 2 mm glutamine, and 1% antibiotic-antimycotic. Maintained at 37 ° C. in an atmosphere moistened with 95% air and 5% CO ₂ . Briefly, HT-29 cells are placed in a 96-well microtiter plate at a density of 500 cells / well and incubated for 24 hours at 37 ° C. before the compound is added. Each cell number determination includes 6 iterations. After 6 days of culture, the cells were fixed by the addition of 10% final concentration of cold trichloroacetic acid, and the protein levels were determined by Skhan, P., incorporated herein by reference. , Storeng, R .; , Scuderia, D .; Monks, A .; McMahon, J .; Vistica, D .; , Warren, J .; T.A. Bokesch, H .; Kenney, S .; , And Boyd, M .; R. , “New Colorimetric Assay for Anticancer-Drug Screening,” J. Am. Natl. Cancer Inst. 82: 1107-1112, 1990, measured using the sulforhodamine B (SRB) colorimetric protein staining assay previously described.

  In addition to the SRB assay described above, many other methods are available for measuring growth inhibition and can be substituted for the SRB assay. These methods include counting viable cells after trypan blue staining, labeling cells capable of DNA synthesis with BrdU or radiolabeled thymidine, neutral red staining of viable cells, or MTT staining of viable cells.

Inhibition of significant tumor cell growth greater than about 50% at a therapeutically effective dose indicates that the composition is useful for treating malignant neoplastic destruction.
Example 2 Breast Organ Culture Model Test The composition can also be tested for antineoplastic activity by its ability to inhibit the occurrence of premalignant neoplastic destruction in the mammary organ culture system. This mouse mammary organ culture technique has been favored by other researchers to study the effects of known antineoplastic agents such as certain NSAIDs, retinoids, tamoxifen, selenium, and certain natural products. Used in the results.

  For example, female BALB / c mice can be treated daily with a combination of estradiol and progesterone to prime the glands to react with hormones in vitro. Mice are sacrificed and the breast mammary gland is excised aseptically and incubated for 10 days in growth medium supplemented with insulin, prolactin, hydrocortisone, and aldosterone. DMBA (7,12 dimethylbenzo (a) anthracene) is added to the medium to induce the formation of premalignant neoplastic destruction. The fully developed gland is then deprived of prolactin, hydrocortisone, and aldosterone, leading to gland regression, but not to regression of premalignant neoplastic destruction.

  Test compounds are dissolved in DMSO and added to the culture medium during the culture period. At the end of the culture period, the glands are fixed in 10% formalin, stained with alum carmine and placed on a glass slide. The incidence of formation of mammary gland destruction is the ratio of glands with mammary gland destruction to glands without destruction. The incidence of mammary gland destruction in glands treated with the test composition is compared to that of untreated glands.

  The extent of the area occupied by mammary gland destruction can be quantified by projecting the glandular image onto a digitized pad. The area covered by the gland is tracked on the pad and considered as 100% area. The area covered by each non-regressive structure is further outlined on the digitizing pad and quantified by the computer.

Claims (120)

  A method for the treatment of malignant tumors in a patient comprising the steps of: selecting a cyclooxygenase-2 selective inhibitor or pharmaceutically acceptable salt or prodrug thereof; and a carbonic anhydrase inhibitor or pharmaceutically Said method comprising administering an acceptable salt or prodrug.   2. The method of claim 1, wherein the carbonic anhydrase inhibitor comprises benzothiazole sulfonamide. The carbonic anhydrase inhibitor has the following formula:

[Where:
Each R ₁ is hydrogen, lower alkyl, halogen, nitro, trihaloalkyl, lower alkoxy, formyl, lower alkanoyl lower alkylamino or di-lower alkylamino;
R ₆ is hydrogen or lower alkyl;
Y ₁ represents the following formula:

And in the formula:
X ₁ is O or NR ₅ or S;
R ₂ is OR ₇ or NR ₇ R ₈ ;
Each R ₃ and R ₄ is hydrogen or lower alkyl;
R ₅ , R ₇ and R ₈ are independently hydrogen or lower alkyl;
m is an integer that is 0, 1, 2, 3, 4, 5, or 6; and n is an integer that is 0, 1, 2, or 3;
3. The method of claim 2, comprising a compound having Carbonic anhydrase inhibitors include:
a) 6-hydroxy-2-benzothiazolesulfonamide;
b) 6- (ethyloxalyloxy) -2-benzothiazolesulfonamide;
c) 6- (ethylsuccinyloxy) -2-benzothiazolesulfonamide;
d) The following formula:

And e) the following formula:

;
4. The method of claim 3, wherein the method is selected from the group consisting of: The carbonic anhydrase inhibitor has the following formula:

[Where:
Z ₁ represents a water-soluble carrier, and A ₁ still possesses carbonic anhydrase inhibitory activity, but further forms an enzymatically cleavable bond between A ₁ and Z _1. It is a part connected to a carbonic anhydrase inhibitor.
3. The method of claim 2, comprising a compound having   The method of claim 1, wherein the carbonic anhydrase inhibitor comprises hydroxymetazolamide. The carbonic anhydrase inhibitor has the following formula:

[Where:
Z ₂ represents a water-soluble carrier,
n is 1, 2, 3, 4, or a 5; and A _2, This is to still retain the carbonic anhydrase inhibition activity, but an enzymatically cleavable bond between _{A 2} and _{Z 2} A moiety connected to a carbonic anhydrase inhibitor that also makes it possible to form;
7. A method according to claim 6 comprising a compound having The carbonic anhydrase inhibitor has the following formula:

[Where:
Z ₃ represents a water-soluble carrier; and A ₃ still possesses carbonic anhydrase inhibitory activity, but further forms an enzymatically cleavable bond between A ₃ and Z _3. Enabling, a moiety connected to a carbonic anhydrase inhibitor;]
The method of claim 1, comprising a compound having: The carbonic anhydrase inhibitor has the following formula:

[Where:
n is an integer that is 0, 1, 2, 3, 4, or 5;
X ₂ is hydrogen, hydroxyl, hydroxylmethyl, 2-hydroxyethyl, or 2-hydroxyethoxy;
Ar ₁ is phenyl, pyridyl, or furanyl; and m is an integer that is 0, 1, 2, 3, or 4;
The method of claim 1, comprising a compound having:   2. The method of claim 1, wherein the carbonic anhydrase inhibitor comprises thiophene sulfonamide. The carbonic anhydrase inhibitor has the following formula:

[Where:
R ₉ is H, C _1-4 alkyl, C _2-4 alkyl optionally substituted with OH, halogen, C _1-4 alkoxy, or C (═O) R ₁₅ ;
R ₁₀ is H; C _1-8 alkyl, OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C _2-8 alkyl substituted with C (═O) R ₁₅ ; C _3-7 alkenyl optionally substituted with OH, NR ₁₃ R ₁₄ , or C _1-4 alkoxy; unsubstituted or optionally substituted with OH, NR ₁₃ R ₁₄ , or C _1-4 alkoxy C _3-7 alkynyl; unsubstituted or optionally OH, (CH ₂ ) _n NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₁₅ , S (═O) _m R ₁₆ , or C _1-3 alkyl substituted with phenyl or heteroaryl, which can be substituted with SO ₂ NR ₁₃ R ₁₄ , where m Is 0-2 and n is 0-2; C _2-4 alkoxy optionally substituted with NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy, or C (═O) R ₁₅ ; OH, (CH ₂ ) _n NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₁₅ , S (═O) _m R ₁₆ Or phenyl substituted by SO ₂ NR ₁₃ R ₁₄ , or heteroaryl, where m is 0-2 and n is 0-2; provided that both R ₉ and R ₁₀ are H Or R ₉ and R ₁₀ can be joined to form a saturated ring of 5 or 6 atoms selected from O, S, C or N, which is Not replaced or replaced OH on carbon _{by, NR} 13 _{R 14, halogen, C 1-4 alkoxy, C (= O) R 15} , C 1-6 alkyl, optionally _{OH, NR} 13 _{R 14, halogen, C 1-4} alkoxy, C (= _O) by _{C 1-6} alkyl substituted with _{R 15,} or a nitrogen _NR 13 _{R 14, C 1-4 alkoxy, C (= O) R 15} , C 1-6 alkyl or optionally OH, NR Can be substituted with C _2-6 alkyl substituted with ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R ₁₅ ;
R ₁₁ is H; halogen; C _1-4 alkyl; C _1-8 alkoxy; C _1-8 alkyl thiol; optionally OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R C _2-8 alkoxy substituted with ₁₅ ; C _1-4 alkyl optionally substituted with R ₁₂ ; or R ₉ and R ₁₁ are joined together with a carbon atom to form a 5- to 7-membered ring Wherein the carbon atom can be unsubstituted or optionally substituted with R ₁₂ ;
R ₁₂ is OH; C _1-4 alkyl, unsubstituted or optionally substituted with OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R ₁₅ ; C _1-4 Alkoxy; C _2-4 alkoxy optionally substituted with OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R ₁₅ ; NR ₁₃ R ₁₄ ; unsubstituted or optionally OH , (CH ₂ ) _n NR ₁₃ R ₁₄ , substituted with halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₁₅ , S (═O) R ₁₆ or SO ₂ NR ₁₃ R ₁₄ Phenyl or heteroaryl, wherein m is 0-2 and n is 0-2;
R ₁₃ and R ₁₄ are the same or different and are H; C _1-4 alkyl; C _2-4 alkyl optionally substituted with OH, halogen, C _1-4 alkoxy or C (═O) R ₁₅ C _1-4 alkoxy; C _2-4 alkoxy optionally substituted with OH, halogen, C _1-4 alkoxy or C (═O) R ₁₅ ; unsubstituted or optionally OH, NR ₁₃ R _14; , or _{C 1-4 C 3-7} alkenyl substituted by alkoxy; unsubstituted or optionally _{OH, NR} 13 _{R 14,} or _{C 3-7} alkynyl substituted with _{C 1-4} alkoxy; _{C 1} There _-2 alkyl _{C 3-5} cycloalkyl; or _{R 13} and _{R 14} are bonded, to form O, S, a 5- or 6 atoms selected from C or N Can, which is either unsubstituted or optionally OH at carbon, (= O), OH _{halogen, C 1-4 alkoxy, C (= O) R 15} , C 1-6 alkyl, optionally halogen , C _1-4 alkoxy, C _1-6 alkyl substituted with C (═O) R ₁₅ , or at nitrogen, C _1-4 alkoxy, C (═O) R ₁₅ , S (═O) _m R ₁₆ , C _1-6 alkyl or optionally substituted with OH, halogen, C _1-4 alkoxy, C _2-6 alkyl substituted with C (═O) R ₁₅ , or in sulfur with (═O) _m Where m is 0-2;
R _{15 is, C 1-8} alkyl; optionally _{OH, NR} 13 _{R 14, halogen, C 1-4} alkoxy or _C (= _O) C substituted with _{R 17 1-8 alkyl; C 1-4} alkoxy; C _2-4 alkoxy optionally substituted with OH, NR ₁₃ R ₁₄ , halogen or C _1-4 alkoxy; or NR ₁₃ R ₁₄ ;
R ₁₆ is C _1-4 alkyl; optionally C _2-4 alkyl substituted with OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R ₁₅ ; and R ₁₇ C _1-4 alkyl; C _1-4 alkoxy; amino, C _1-3 alkylamino, or di-C _1-3 alkylamino; and G ₁ is C (═O) or SO ₂ ; ]
12. The method of claim 10, comprising a compound having   2. The method of claim 1, wherein the carbonic anhydrase inhibitor comprises thienothiazine sulfonamide. The carbonic anhydrase inhibitor or a pharmaceutically acceptable salt or prodrug thereof has the following formula:

[Where:
R ₁₈ and R ₁₉ are H or C _1-4 alkyl;
R ₂₀ is C _1-6 alkyl, CH ₂ (CH ₂ ) _n OR ₂₁ , where n is 1-4; and R ₂₁ is CH ₃ , n is 1-4 (CH _{2 N} CH ₃ or (CH ₂ ) _n Ar ₂ , wherein Ar ₂ is unsubstituted phenyl, 3-methoxyphenyl, or 4-methoxyphenyl, and n is 1 or 2;
13. A method according to claim 12, comprising a compound having The carbonic anhydrase inhibitor has the following formula:

[Where:
R ₂₂ is C _1-6 , substituted with H, unsubstituted or optionally substituted with OH, C _1-4 alkoxy, NR ₂₄ R ₂₅ , OC (═O) R ₂₆ or C (═O) R _26. Is alkyl;
R ₂₃ is H; C _1-8 alkyl; OH, NR ₂₄ R ₂₅ , halogen, C _1-4 alkoxy, C _2-4 alkoxy, C _1-4 alkoxy, OC (═O) R ₂₆ , S (= O) _m R ₂₈ , or C _1-8 alkyl substituted with C (═O) R ₂₆ ; C unsubstituted or optionally substituted with OH, NR ₂₄ R ₂₅ , or C _1-4 alkoxy _3-7 alkenyl; C _3-7 alkynyl which is unsubstituted or optionally substituted with OH, NR ₂₄ R ₂₅ , or C _1-4 alkoxy; unsubstituted or optionally C _1-3 alkyl; C _{1-3 haloalkyl, OH, (CH 2) n} NR 24 R 25, _{halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, OC (= O) R 26} , C (= O) R 26, S = _O) a _{C 0-3} alkyl substituted with _{R 27,} which may be substituted with _{m R 28} or _SO 2 _NR 24 _{R 25,} m wherein is 0-2, and n is 0 2;
R ₂₄ and R ₂₅ are independently H; C _1-8 alkyl; C _2-4 alkyl optionally substituted with OH, halogen, C _1-4 alkoxy or C (═O) R ₂₆ ; OH; C _{1 -4} alkoxy; optionally OH, halogen, C _1-4 alkoxy or C _2-4 alkoxy substituted with C (═O) R ₂₆ ; or R ₂₄ and R ₂₅ are joined to form O, A ring of 5 or 6 atoms selected from S, C or N can be formed, which is unsubstituted or optionally OH at the carbon, (= O), halogen, C _{1- 4} alkoxy, C (═O) R ₂₆ , C _1-6 alkyl, optionally OH, halogen, C _1-4 alkoxy, C _1-6 alkyl substituted with C (═O) R ₂₆ , or at nitrogen C _1-4 alkoxy, C In _{= O) R 26, S (} = O) m R 28, C 1-6 alkyl or optionally OH, _{halogen, C 1-4} alkoxy, _C (= _O) C _2-6 alkyl substituted with _{R 26} Or can be substituted by (═O) _m in sulfur, where m is 0-2;
R _{26 is, C 1-8} alkyl; optionally _{OH, NR} 24 _{R 25, halogen, C 1-4} alkoxy or _C (= _O) C substituted with _{R 29 1-4 alkyl; C 1-4} alkoxy; Optionally OH, NR ₂₄ R ₂₅ , halogen or C _1-4 alkoxy substituted C _2-4 alkoxy; or NR ₂₄ R ₂₅ ;
R ₂₇ is from C, N, O or S such as benzene, furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine pyrimidine, pyridazine, and pyrazine. Is a monocyclic ring system of 5 or 6 atoms composed of;
R ₂₈ is C _1-4 alkyl; C _2-4 alkyl optionally substituted with OH, NR ₂₄ R ₂₅ , C _1-4 alkoxy or C (═O) R ₂₆ ; unsubstituted or optionally OH, (CH ₂ ) _n NR ₂₄ R ₂₅ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₂₆ , S (═O) _m C _1-4 alkyl or SO ₂ NR R ₂₇ which can be substituted with ₂₄ R ₂₅ ; where m is 0-2 and n is 0-2; and R ₂₉ is C _1-4 alkyl; C _1-4 Alkoxy; amino, C _1-3 alkylamino, di-C _1-3 alkylamino;
13. A method according to claim 12, comprising a compound having The carbonic anhydrase inhibitor has the following formula:

[Where:
R ₄₇ is, H; _{OH; C 1-6} alkoxy; unsubstituted or optionally _{OH, NR 49 R 50, OC} (= O) R 51 or _C (= _O) C ₁ substituted with _{R 51 -6 alkyl; NR 49 R 50; OC (} = O) R 51; C (= O) R 51; optionally _{OH, NR} 49 _{R 50, halogen, C 1-4} alkoxy or C (= _{O) R 51} Substituted C _2-4 alkoxy; any of these are unsubstituted or optionally OH, (CH ₂ ) _n NR ₄₉ R ₅₀ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (= O) R ₅₁ , S (= O) _m R ₅₃ or SO ₂ NR ₄₉ R ₅₀ is phenyl or R ₅₂ ; where _m is 0-2 and n Is 0-2 There proviso _that when _{R 47} is OH, _{alkoxy, NR} 49 _{R 50,} or OC (= _{O) R 51,} which are connected to the 4-position, and _{R 47} is _{R 52,} and 3-position connection The R ₅₂ rings are connected by a carbon-carbon single bond;
R _{48 is, S (= O) m C} 2-8 alkyl substituted with _{R 53;} a S ₍₌ O) _{C 4-7} alkenyl substituted with _{m R 53,} wherein m is 2-0 Yes;
R ₄₉ and R ₅₀ are H; C _1-8 alkyl; C _2-4 alkyl optionally substituted with OH, halogen, C _1-4 alkoxy or C (═O) R ₅₁ ; C _1-4 alkoxy; Is C _2-4 alkoxy optionally substituted with OH, halogen, C _1-4 alkoxy, or C (═O) R ₅₁ ; or R ₄₉ and R ₅₀ are joined to form O, S, C Or a ring of 5 or 6 atoms selected from N, which may be unsubstituted or optionally substituted at the carbon with OH, (═O), halogen, C _1-4 alkoxy, _{C (= O) R 51,} C 1-6 alkyl, optionally OH, _{halogen, C 1-4} alkoxy, with _C (= _O) C _1-6 alkyl substituted with _{R 51,} or a nitrogen _{C 1- 4} alkoxy, C (= O) R _{1, S (= O) m} R 53, C 1-6 alkyl or optionally OH, _{halogen, C 1-4} alkoxy, with _C (= _O) C _2-6 alkyl substituted with _{R 51,} or in sulfur (= _O) it can be substituted by _m, m wherein is 0-2;
R _{51 is, C 1-8} alkyl; optionally _{OH, NR} 49 _{R 50, halogen, C 1-4} alkoxy or _C (= _O) C substituted with _{R 54 1-8 alkyl; C 1-4} alkoxy; C _2-4 alkoxy optionally substituted with OH, NR ₄₉ R ₅₀ , halogen or C _1-4 alkoxy; or NR ₄₉ R ₅₀ ;
R ₅₂ is composed of C, N, O or S such as furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine pyrimidine, pyridazine, and pyrazine. A monocyclic ring system of 5 or 6 atoms;
R ₅₃ is C _1-4 alkyl; C _3-5 alkenyl, optionally C _2-4 alkyl substituted with OH, NR ₄₉ R ₅₀ , C _1-4 alkoxy or C (═O) R ₅₁ ; Either is unsubstituted or optionally OH, (CH ₂ ) _n NR ₄₉ R ₅₀ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₅₁ , S (= O) _m C _1-4 alkyl or SO ₂ NR ₄₉ R ₅₀ can be substituted with phenyl or R ₅₂ ;
m is 0-2 and n is 0-2; and R ₅₄ is C _1-4 alkyl; C _1-4 alkoxy; amino, C _1-3 alkylamino, or di-C _1-3 Alkylamino;
The method according to claim 10, comprising the compound of: The carbonic anhydrase inhibitor has the following formula:

[Where:
A ₄ is carbon or nitrogen;
Z ₅ is NHR ₆₅ or OR ⁶⁵ ;
R ⁶⁵ is either straight or branched C _1-6 alkyl;
R ⁶⁶ is hydrogen, C _1-3 alkyl, or C _1-4 alkoxy-C _1-4 alkyl; and X ₃ is S (O) ₂ or C (O) ₂ ;
12. The method of claim 10, comprising a compound having   The method of claim 1, wherein the carbonic anhydrase inhibitor is acetazolamide.   The method of claim 1, wherein the carbonic anhydrase inhibitor is metazolamide.   The method of claim 1, wherein the carbonic anhydrase inhibitor is diclofenamide.   The method of claim 1, wherein the carbonic anhydrase inhibitor is dorzolamide.   The method of claim 1, wherein the carbonic anhydrase inhibitor is brinzolamide.   2. The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor or pharmaceutically acceptable salt or prodrug thereof comprises a chromene compound.   23. The method of claim 22, wherein the chromene compound is benzopyran or a substituted benzopyran analog.   24. The method of claim 23, wherein the benzopyran or substituted benzopyran analog is selected from the group consisting of benzothiopyrans, dihydroquinolines and dihydronaphthalenes.   2. The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor or pharmaceutically acceptable salt or prodrug thereof comprises a tricyclic compound.   26. The method of claim 25, wherein the tricyclic compound comprises benzenesulfonamide or methylsulfonylbenzene.   The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof comprises a phenylacetic acid derivative. Said cyclooxygenase-2 selective inhibitor has the following formula:

The method of claim 1 comprising: Said cyclooxygenase-2 selective inhibitor has the following formula:

The method of claim 1 comprising: Said cyclooxygenase-2 selective inhibitor has the following formula:

[Where:
n is an integer that is 0, 1, 2, 3 or 4;
G is O, S or NR ^a ;
R ^a is alkyl;
R ¹ is selected from the group consisting of H and aryl;
R ² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
R ³ is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and each R ⁴ is , H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, Amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, hete Independently from the group consisting of cyclosulfonyl, alkylsulfonyl, hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl Selected;
Where R ⁴ together with the carbon atom to which it is attached and the remainder of ring E form a naphthyl radical;
The method according to claim 1, comprising: R ¹ is H;
R ² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
R ³ is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl, wherein each of haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl is selected from the group consisting of alkylthio, nitro, and alkylsulfonyl. Optionally independently substituted with one or more radicals; and each R ⁴ is hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, halo Alkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylamido Sulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl And independently selected from the group consisting of alkylcarbonyl; or R ⁴ together with ring E forms a naphthyl radical;
The method of claim 30. G is oxygen or sulfur;
R ¹ is H;
R ² is carboxyl, lower alkyl, lower aralkyl or lower alkoxycarbonyl;
R ³ is lower haloalkyl, lower cycloalkyl or phenyl; and each R ⁴ is H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, Lower alkylaminosulfonyl, 5 membered heteroarylalkylaminosulfonyl, 6 membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5 membered nitrogen containing heterocyclosulfonyl, 6 membered nitrogen containing heterocyclosulfonyl, lower alkylsulfonyl, Optionally substituted phenyl, lower aralkylcarbonyl, or lower alkylcarbonyl; or wherein R ⁴ forms a naphthyl radical together with the carbon atom to which it is attached and the remainder of ring E. Complete;
The method of claim 30. R ² is carboxyl;
R ³ is lower haloalkyl; and each R ⁴ is H, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkyl Is aminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, or lower alkylcarbonyl; or Where R ⁴ together with ring E forms a naphthyl radical;
The method of claim 30. R ³ is fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, or trifluoromethyl; and the respective R ⁴ is H, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluoromethyl, difluoromethyl, trifluoro Methoxy, amino, N, N-dimethylamino, N, N-diethylamino, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N- (2-furylmethyl) a Nosulfonyl, nitro, N, N-dimethylaminosulfonyl, aminosulfonyl, N-methylaminosulfonyl, N-ethylsulfonyl, 2,2-dimethylethylaminosulfonyl, N, N-dimethylaminosulfonyl, N- (2-methyl) Propyl) aminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl or phenyl; or wherein R ⁴ is the carbon atom to which it is attached and the ring E Forms a naphthyl radical with the remainder;
The method of claim 30. Said cyclooxygenase-2 selective inhibitor has the following formula:

[Where:
G is oxygen or sulfur;
R ⁸ is trifluoromethyl or pentafluoroethyl;
R ⁹ is H, chloro, or fluoro;
R ¹⁰ is H, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, benzylaminosulfonyl, phenylethylaminosulfonyl, Methylpropylaminosulfonyl, methylsulfonyl, or morpholinosulfonyl;
R ¹¹ is H, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, or phenyl; and R ¹² is H, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, Or phenyl;
32. The method of claim 30, comprising the compound of: Said cyclooxygenase-2 selective inhibitor has the following formula:

[Where:
A is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclyl ring;
R ₁ is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R ¹ is alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, Optionally substituted at substitutable positions with one or more radicals selected from arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
R ₂ is selected from the group consisting of methyl or amino; and R ₃ is H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cyclo Alkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, Aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocal Nilalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkyl Amino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, Aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, aryl Ruhoniru is selected from the group consisting of radicals chosen from N- alkyl -N- arylaminosulfonyl;]
The method according to claim 1, comprising: Said cyclooxygenase-2 selective inhibitor has the following formula:

The method of claim 1 comprising: Said cyclooxygenase-2 selective inhibitor has the following formula:

The method of claim 1 comprising:   2. The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor comprises 4- [4- (methyl) -sulfonyl) phenyl] -3-phenyl-2 (5H) -furanone.   2. The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor comprises 4- (5-methyl-3-phenyl-4-isoxazolyl).   2. The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor comprises 2- (6-methylpyrid-3-yl) -3- (4-methylsulfonylphenyl) -5-chloropyridine.   2. The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor comprises 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl]. .   The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor comprises N-[[4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonyl].   The cyclooxygenase-2 selective inhibitor comprises 4- [5- (3-fluoro-4-methoxyphenyl) -3-difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide. The method according to 1.   The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor comprises (S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid. .   The cyclooxygenase-2 selective inhibitor is 2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) The method of claim 1 comprising pyridazinone. Said cyclooxygenase-2 selective inhibitor has the following formula:

[Where:
R ¹⁶ is methyl or ethyl;
R ¹⁷ is chloro or fluoro;
R ¹⁸ is hydrogen or fluoro;
R ¹⁹ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy;
R ²⁰ is hydrogen or fluoro; and R ²¹ is chloro, fluoro, trifluoromethyl or methyl;
Provided that when R ¹⁶ is ethyl and R ¹⁹ is H, R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are not all fluoro;
The method according to claim 1, comprising: R ¹⁶ is ethyl;
R ¹⁷ and R ¹⁹ are chloro;
R ¹⁸ and R ²⁰ are hydrogen; and R ²¹ is methyl;
48. The method of claim 47. Said cyclooxygenase-2 selective inhibitor has the following formula:

[Where:
X is O or S;
J is a carbocyclic or heterocyclic ring;
R ²² is NHSO ₂ CH ₃ or F;
R ²³ is H, NO ₂ , or F; and R ²⁴ is H, NHSO ₂ CH ₃ , or (SO ₂ CH ₃ ) C ₆ H ₄ ;]
The method according to claim 1, comprising: Said cyclooxygenase-2 selective inhibitor has the following formula:

[Where:
T and M are independently a radical derived from a heterocycle containing phenyl, naphthyl, 5 to 6 members and carrying 1 to 4 heteroatoms, or saturated with 3 to 7 carbon atoms. A radical derived from a hydrocarbon ring;
Q ¹ , Q ² , L ¹ or L ² is independently hydrogen, halogen, lower alkyl having 1 to 6 carbon atoms, trifluoromethyl, or lower methoxy having 1 to 6 carbon atoms; And at least one of Q ¹ , Q ² , L ¹ or L ² is in the para position and is —S (O) _n —R, wherein n is 0, 1, or 2, and R is 1 or to a lower haloalkyl radical or -SO ₂ NH ₂ with a lower alkyl radical or 1 to 6 carbon atoms having 6 carbon atoms; or
Q ¹ and Q ² are methylenedioxy; or L ¹ and L ² are methylenedioxy; and R ²⁵ , R ²⁶ , R ²⁷ , and R ²⁸ are independently hydrogen, halogen, 1 Is a lower alkyl having 6 to 6 carbon atoms, a lower haloalkyl having 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl; or R ²⁵ And R ²⁶ is O; or R ²⁷ and R ²⁸ are O; or R ²⁵ and R ²⁶ together with the carbon atom to which they are attached 3-7 carbon atoms. or form a saturated hydrocarbon ring having; or R ^27, R ²⁸ is a saturated hydrocarbon having to these 3 free together with the carbon atoms connecting 7 carbon atoms To form a ring;]
The method according to claim 1, comprising:   2. The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib, valdecoxib, etoroxib, parecoxib, and deracoxib.   The method of claim 1, wherein the malignant tumor is colorectal cancer.   The method of claim 1, wherein the malignant tumor is gastric cancer.   The method of claim 1, wherein the malignant tumor is liver cancer.   The method of claim 1, wherein the malignant tumor is bladder cancer.   The method of claim 1, wherein the malignant tumor is cervical cancer.   The method of claim 1, wherein the malignant tumor is prostate cancer.   The method of claim 1, wherein the malignant tumor is lung cancer.   The method of claim 1, wherein the malignant tumor is breast cancer.   The method of claim 1, wherein the malignant tumor is skin cancer.   The method of claim 1, wherein the malignant tumor is an adenomatous polyp.   The method of claim 1, wherein the patient is a mammal.   64. The method of claim 62, wherein the mammal is a human.   64. The method of claim 62, wherein the mammal is a companion animal.   65. The method of claim 64, wherein the companion animal is a dog or a cat.   A composition for the treatment of a malignant tumor in a patient, said cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof, and a carbonic anhydrase inhibitor or a pharmaceutical thereof Administering an acceptable salt or prodrug to the composition.   68. The method of claim 66, wherein the carbonic anhydrase inhibitor comprises benzothiazole sulfonamide. The carbonic anhydrase inhibitor has the following formula:

[Where:
Each R ₁ is hydrogen, lower alkyl, halogen, nitro, trihaloalkyl, lower alkoxy, formyl, lower alkanoyl lower alkylamino or di-lower alkylamino;
R ₆ is hydrogen or lower alkyl;
Y ₁ represents the following formula:

And in the formula:
X ₁ is O or NR ₅ or S;
R ₂ is OR ₇ or NR ₇ R ₈ ;
Each R ₃ and R ₄ is hydrogen or lower alkyl;
R ₅ , R ₇ and R ₈ are independently hydrogen or lower alkyl;
m is an integer that is 0, 1, 2, 3, 4, 5, or 6; and n is an integer that is 0, 1, 2, or 3;
68. The composition of claim 67, comprising a compound having: The carbonic anhydrase inhibitor has the following formula:

[Where:
Z ₁ represents a water-soluble carrier, and A ₁ still possesses carbonic anhydrase inhibitory activity, but further forms an enzymatically cleavable bond between A ₁ and Z _1. Enabling, a moiety connected to a carbonic anhydrase inhibitor;]
68. The composition of claim 67, comprising a compound having:   68. The method of claim 66, wherein the carbonic anhydrase inhibitor comprises hydroxymetazolamide. The carbonic anhydrase inhibitor has the following formula:

[Where:
Z ₂ represents a water-soluble carrier,
n is 1, 2, 3, 4, or a 5; and A _2, This is to still retain the carbonic anhydrase inhibition activity, but an enzymatically cleavable bond between _{A 2} and _{Z 2} A moiety connected to a carbonic anhydrase inhibitor that also makes it possible to form;
72. The composition of claim 70, comprising a compound having: The carbonic anhydrase inhibitor has the following formula:

[Where:
Z ₃ represents a water-soluble carrier; and A ₃ still possesses carbonic anhydrase inhibitory activity, but further forms an enzymatically cleavable bond between A ₃ and Z _3. Enabling, a moiety connected to a carbonic anhydrase inhibitor;]
68. The composition of claim 66, comprising a compound having: The carbonic anhydrase inhibitor has the following formula:

[Where:
n is an integer that is 0, 1, 2, 3, 4, or 5;
X ₂ is hydrogen, hydroxyl, hydroxylmethyl, 2-hydroxyethyl, or 2-hydroxyethoxy;
Ar ₁ is phenyl, pyridyl, or furanyl; and m is an integer that is 0, 1, 2, 3, or 4;
68. The composition of claim 66, comprising a compound having:   68. The composition of claim 66, wherein the carbonic anhydrase inhibitor comprises thiophene sulfonamide. The carbonic anhydrase inhibitor has the following formula:

[Where:
R ₉ is H, C _1-4 alkyl, C _2-4 alkyl optionally substituted with OH, halogen, C _1-4 alkoxy, or C (═O) R ₁₅ ;
R ₁₀ is H; C _1-8 alkyl, OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C _2-8 alkyl substituted with C (═O) R ₁₅ ; C _3-7 alkenyl optionally substituted with OH, NR ₁₃ R ₁₄ , or C _1-4 alkoxy; unsubstituted or optionally substituted with OH, NR ₁₃ R ₁₄ , or C _1-4 alkoxy C _3-7 alkynyl; unsubstituted or optionally OH, (CH ₂ ) _n NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₁₅ , S (═O) _m R ₁₆ , or C _1-3 alkyl substituted with phenyl or heteroaryl, which can be substituted with SO ₂ NR ₁₃ R ₁₄ , where m Is 0-2 and n is 0-2; C _2-4 alkoxy optionally substituted with NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy, or C (═O) R ₁₅ ; OH, (CH ₂ ) _n NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₁₅ , S (═O) _m R ₁₆ Or phenyl substituted by SO ₂ NR ₁₃ R ₁₄ , or heteroaryl, where m is 0-2 and n is 0-2; provided that both R ₉ and R ₁₀ are H Or R ₉ and R ₁₀ can be joined to form a saturated ring of 5 or 6 atoms selected from O, S, C or N, which is Not replaced or replaced OH on carbon _{by, NR} 13 _{R 14, halogen, C 1-4 alkoxy, C (= O) R 15} , C 1-6 alkyl, optionally _{OH, NR} 13 _{R 14, halogen, C 1-4} alkoxy, C (= _O) by _{C 1-6} alkyl substituted with _{R 15,} or a nitrogen _NR 13 _{R 14, C 1-4 alkoxy, C (= O) R 15} , C 1-6 alkyl or optionally OH, NR Can be substituted with C _2-6 alkyl substituted with ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R ₁₅ ;
R ₁₁ is H; halogen; C _1-4 alkyl; C _1-8 alkoxy; C _1-8 alkyl thiol; optionally OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R C _2-8 alkoxy substituted with ₁₅ ; C _1-4 alkyl optionally substituted with R ₁₂ ; or R ₉ and R ₁₁ are joined together with a carbon atom to form a 5- to 7-membered ring Wherein the carbon atom can be unsubstituted or optionally substituted with R ₁₂ ;
R ₁₂ is OH; C _1-4 alkyl, unsubstituted or optionally substituted with OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R ₁₅ ; C _1-4 Alkoxy; C _2-4 alkoxy optionally substituted with OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R ₁₅ ; NR ₁₃ R ₁₄ ; unsubstituted or optionally OH , (CH ₂ ) _n NR ₁₃ R ₁₄ , substituted with halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₁₅ , S (═O) R ₁₆ or SO ₂ NR ₁₃ R ₁₄ Phenyl or heteroaryl, wherein m is 0-2 and n is 0-2;
R ₁₃ and R ₁₄ are the same or different and are H; C _1-4 alkyl; C _2-4 alkyl optionally substituted with OH, halogen, C _1-4 alkoxy or C (═O) R ₁₅ C _1-4 alkoxy; C _2-4 alkoxy optionally substituted with OH, halogen, C _1-4 alkoxy or C (═O) R ₁₅ ; unsubstituted or optionally OH, NR ₁₃ R _14; , or _{C 1-4 C 3-7} alkenyl substituted by alkoxy; unsubstituted or optionally _{OH, NR} 13 _{R 14,} or _{C 3-7} alkynyl substituted with _{C 1-4} alkoxy; _{C 1} There _-2 alkyl _{C 3-5} cycloalkyl; or _{R 13} and _{R 14} are bonded, to form O, S, a 5- or 6 atoms selected from C or N Can, which is either unsubstituted or optionally OH at carbon, (= O), OH _{halogen, C 1-4 alkoxy, C (= O) R 15} , C 1-6 alkyl, optionally halogen , C _1-4 alkoxy, C _1-6 alkyl substituted with C (═O) R ₁₅ , or at nitrogen, C _1-4 alkoxy, C (═O) R ₁₅ , S (═O) _m R ₁₆ , C _1-6 alkyl or optionally substituted with OH, halogen, C _1-4 alkoxy, C _2-6 alkyl substituted with C (═O) R ₁₅ , or in sulfur with (═O) _m Where m is 0-2;
R _{15 is, C 1-8} alkyl; optionally _{OH, NR} 13 _{R 14, halogen, C 1-4} alkoxy or _C (= _O) C substituted with _{R 17 1-8 alkyl; C 1-4} alkoxy; C _2-4 alkoxy optionally substituted with OH, NR ₁₃ R ₁₄ , halogen or C _1-4 alkoxy; or NR ₁₃ R ₁₄ ;
R ₁₆ is C _1-4 alkyl; optionally C _2-4 alkyl substituted with OH, NR ₁₃ R ₁₄ , halogen, C _1-4 alkoxy or C (═O) R ₁₅ ; and R ₁₇ C _1-4 alkyl; C _1-4 alkoxy; amino, C _1-3 alkylamino, or di-C _1-3 alkylamino; and G ₁ is C (═O) or SO ₂ ; ]
75. The composition of claim 74, comprising a compound having:   68. The composition of claim 66, wherein the carbonic anhydrase inhibitor comprises thienothiazine sulfonamide. The carbonic anhydrase inhibitor has the following formula:

[Where:
R ₁₈ and R ₁₉ are H or C _1-4 alkyl;
R ₂₀ is C _1-6 alkyl, CH ₂ (CH ₂ ) _n OR ₂₁ , where n is 1-4; and R ₂₁ is CH ₃ , n is 1-4 (CH _{2 N} CH ₃ or (CH ₂ ) _n Ar ₂ , wherein Ar ₂ is unsubstituted phenyl, 3-methoxyphenyl, or 4-methoxyphenyl, and n is 1 or 2;
77. The composition of claim 76, comprising a compound having: The carbonic anhydrase inhibitor has the following formula:

[Where:
R ₂₂ is H, C _1-6 unsubstituted or optionally substituted with OH, C _1-4 alkoxy, NR ₂₃ R ₂₅ , OC (═O) R ₂₆ or C (═O) R _26. Is alkyl;
R ₂₃ is H; C _1-8 alkyl; OH, NR ₂₄ R ₂₅ , halogen, C _1-4 alkoxy, C _2-4 alkoxy, C _1-4 alkoxy, OC (═O) R ₂₆ , S (= O) _m R ₂₈ , or C _1-8 alkyl substituted with C (═O) R ₂₆ ; C unsubstituted or optionally substituted with OH, NR ₂₄ R ₂₅ , or C _1-4 alkoxy _3-7 alkenyl; C _3-7 alkynyl which is unsubstituted or optionally substituted with OH, NR ₂₄ R ₂₅ , or C _1-4 alkoxy; unsubstituted or optionally C _1-3 alkyl; C _{1-3 haloalkyl, OH, (CH 2) n} NR 24 R 25, _{halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, OC (= O) R 26} , C (= O) R 26, S = _O) a _{C 0-3} alkyl substituted with _{R 27,} which may be substituted with _{m R 28} or _SO 2 _NR 24 _{R 25,} m wherein is 0-2, and n is 0 2;
R ₂₄ and R ₂₅ are independently H; C _1-8 alkyl; C _2-4 alkyl optionally substituted with OH, halogen, C _1-4 alkoxy or C (═O) R ₂₆ ; OH; C _{1 -4} alkoxy; optionally OH, halogen, C _1-4 alkoxy or C _2-4 alkoxy substituted with C (═O) R ₂₆ ; or R ₂₄ and R ₂₅ are joined to form O, A ring of 5 or 6 atoms selected from S, C or N can be formed, which is unsubstituted or optionally OH at the carbon, (= O), halogen, C _{1- 4} alkoxy, C (═O) R ₂₆ , C _1-6 alkyl, optionally OH, halogen, C _1-4 alkoxy, C _1-6 alkyl substituted with C (═O) R ₂₆ , or at nitrogen C _1-4 alkoxy, C In _{= O) R 26, S (} = O) m R 28, C 1-6 alkyl or optionally OH, _{halogen, C 1-4} alkoxy, _C (= _O) C _2-6 alkyl substituted with _{R 26} Or can be substituted by (═O) _m in sulfur, where m is 0-2;
R _{26 is, C 1-8} alkyl; optionally _{OH, NR} 24 _{R 25, halogen, C 1-4} alkoxy or _C (= _O) C substituted with _{R 29 1-4 alkyl; C 1-4} alkoxy; Optionally OH, NR ₂₄ R ₂₅ , halogen or C _1-4 alkoxy substituted C _2-4 alkoxy; or NR ₂₄ R ₂₅ ;
R ₂₇ is from C, N, O or S such as benzene, furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine pyrimidine, pyridazine, and pyrazine. Is a monocyclic ring system of 5 or 6 atoms composed of;
R ₂₈ is C _1-4 alkyl; C _2-4 alkyl optionally substituted with OH, NR ₂₄ R ₂₅ , C _1-4 alkoxy or C (═O) R ₂₆ ; unsubstituted or optionally OH, (CH ₂ ) _n NR ₂₄ R ₂₅ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₂₆ , S (═O) _m C _1-4 alkyl or SO ₂ NR R ₂₇ which can be substituted with ₂₄ R ₂₅ ; where m is 0-2 and n is 0-2; and R ₂₉ is C _1-4 alkyl; C _1-4 Alkoxy; amino, C _1-3 alkylamino, or di-C _1-3 alkylamino]
77. The composition of claim 76, comprising a compound having: The carbonic anhydrase inhibitor has the following formula:

[Where:
R ₄₇ is, H; _{OH; C 1-6} alkoxy; unsubstituted or optionally _{OH, NR 49 R 50, OC} (= O) R 51 or _C (= _O) C ₁ substituted with _{R 51 -6 alkyl; NR 49 R 50; OC (} = O) R 51; C (= O) R 51; optionally _{OH, NR} 49 _{R 50, halogen, C 1-4} alkoxy or C (= _{O) R 51} Substituted C _2-4 alkoxy; any of these are unsubstituted or optionally OH, (CH ₂ ) _n NR ₄₉ R ₅₀ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (= O) R ₅₁ , S (= O) _m R ₅₃ or SO ₂ NR ₄₉ R ₅₀ is phenyl or R ₅₂ ; where _m is 0-2 and n Is 0-2 There proviso _that when _{R 47} is OH, _{alkoxy, NR} 49 _{R 50,} or OC (= _{O) R 51,} which are connected to the 4-position, and _{R 47} is _{R 52,} and 3-position connection The R ₅₂ rings are connected by a carbon-carbon single bond;
R _{48 is, S (= O) m C} 2-8 alkyl substituted with _{R 53;} a S ₍₌ O) _{C 4-7} alkenyl substituted with _{m R 53,} wherein m is 2-0 Yes;
R ₄₉ and R ₅₀ are H; C _1-8 alkyl; C _2-4 alkyl optionally substituted with OH, halogen, C _1-4 alkoxy or C (═O) R ₅₁ ; C _1-4 alkoxy; Is C _2-4 alkoxy optionally substituted with OH, halogen, C _1-4 alkoxy, or C (═O) R ₅₁ ; or R ₄₉ and R ₅₀ are joined to form O, S, C Or a ring of 5 or 6 atoms selected from N, which may be unsubstituted or optionally substituted at the carbon with OH, (═O), halogen, C _1-4 alkoxy, _{C (= O) R 51,} C 1-6 alkyl, optionally OH, _{halogen, C 1-4} alkoxy, with _C (= _O) C _1-6 alkyl substituted with _{R 51,} or a nitrogen _{C 1- 4} alkoxy, C (= O) R _{1, S (= O) m} R 53, C 1-6 alkyl or optionally OH, _{halogen, C 1-4} alkoxy, with _C (= _O) C _2-6 alkyl substituted with _{R 51,} or in sulfur (= _O) it can be substituted by _m, m wherein is 0-2;
R _{51 is, C 1-8} alkyl; optionally _{OH, NR} 49 _{R 50, halogen, C 1-4} alkoxy or _C (= _O) C substituted with _{R 54 1-8 alkyl; C 1-4} alkoxy; C _2-4 alkoxy optionally substituted with OH, NR ₄₉ R ₅₀ , halogen or C _1-4 alkoxy; or NR ₄₉ R ₅₀ ;
R ₅₂ is composed of C, N, O or S such as furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine pyrimidine, pyridazine, and pyrazine. A monocyclic ring system of 5 or 6 atoms;
R ₅₃ is C _1-4 alkyl; C _3-5 alkenyl, optionally C _2-4 alkyl substituted with OH, NR ₄₉ R ₅₀ , C _1-4 alkoxy or C (═O) R ₅₁ ; Either is unsubstituted or optionally OH, (CH ₂ ) _n NR ₄₉ R ₅₀ , halogen, C _1-4 alkoxy, C _1-4 haloalkoxy, C (═O) R ₅₁ , S (= O) _m C _1-4 alkyl or SO ₂ NR ₄₉ R ₅₀ can be substituted with phenyl or R ₅₂ ;
m is 0-2 and n is 0-2; and R ₅₄ is C _1-4 alkyl; C _1-4 alkoxy; amino, C _1-3 alkylamino, or di-C _1-3 Alkylamino;
67. The composition of claim 66 comprising the compound of: The carbonic anhydrase inhibitor has the following formula:

[Where:
A ₄ is carbon or nitrogen;
Z ₅ is NHR ₆₅ or OR ⁶⁵ ;
R ⁶⁵ is either straight or branched C _1-6 alkyl;
R ⁶⁶ is hydrogen, C _1-3 alkyl, or C _1-4 alkoxy-C _1-4 alkyl; and X ₃ is S (O) ₂ or C (O) ₂ ;
68. The composition of claim 66, comprising a compound having:   68. The composition of claim 66, wherein the cyclooxygenase-2 selective inhibitor comprises a chromene compound.   82. The composition of claim 81, wherein the chromene compound is benzopyran or a substituted benzopyran analog.   83. The composition of claim 82, wherein the benzopyran or substituted benzopyran analog is selected from the group consisting of benzothiopyran, dihydroquinoline and dihydronaphthalene.   68. The composition of claim 66, wherein the cyclooxygenase-2 selective inhibitor or pharmaceutically acceptable salt or prodrug thereof comprises a tricyclic compound.   85. The composition of claim 84, wherein the tricyclic compound comprises benzenesulfonamide or methylsulfonylbenzene.   68. The composition of claim 66, wherein the cyclooxygenase-2 selective inhibitor comprises a phenylacetic acid derivative. Said cyclooxygenase-2 selective inhibitor has the following formula:

68. The composition of claim 66, comprising: Said cyclooxygenase-2 selective inhibitor has the following formula:

68. The composition of claim 66, comprising: Said cyclooxygenase-2 selective inhibitor has the following formula:

[Where:
n is an integer that is 0, 1, 2, 3 or 4;
G is O, S or NR ^a ;
R ^a is alkyl;
R ¹ is selected from the group consisting of H and aryl;
R ² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
R ³ is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and each R ⁴ is , H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, Amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, hete Independently from the group consisting of cyclosulfonyl, alkylsulfonyl, hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl Selected;
Where R ⁴ together with the carbon atom to which it is attached and the remainder of ring E form a naphthyl radical;
67. The composition of claim 66 comprising the compound of: R ¹ is H;
R ² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
R ³ is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl, wherein each of haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl is selected from the group consisting of alkylthio, nitro, and alkylsulfonyl. Optionally independently substituted with one or more radicals; and each R ⁴ is hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, halo Alkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylamido Sulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl And independently selected from the group consisting of alkylcarbonyl; or R ⁴ together with ring E forms a naphthyl radical;
90. The composition of claim 89. G is oxygen or sulfur;
R ¹ is H;
R ² is carboxyl, lower alkyl, lower aralkyl or lower alkoxycarbonyl;
R ³ is lower haloalkyl, lower cycloalkyl or phenyl; and each R ⁴ is H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, Lower alkylaminosulfonyl, 5 membered heteroarylalkylaminosulfonyl, 6 membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5 membered nitrogen containing heterocyclosulfonyl, 6 membered nitrogen containing heterocyclosulfonyl, lower alkylsulfonyl, Optionally substituted phenyl, lower aralkylcarbonyl, or lower alkylcarbonyl; or wherein R ⁴ forms a naphthyl radical together with the carbon atom to which it is attached and the remainder of ring E. Complete;
90. The composition of claim 89. R ² is carboxyl;
R ³ is lower haloalkyl; and each R ⁴ is H, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkyl Is aminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, or lower alkylcarbonyl; or Where R ⁴ together with ring E forms a naphthyl radical;
90. The composition of claim 89. R ³ is fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, or trifluoromethyl; and the respective R ⁴ is H, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluoromethyl, difluoromethyl, trifluoro Methoxy, amino, N, N-dimethylamino, N, N-diethylamino, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N- (2-furylmethyl) a Nosulfonyl, nitro, N, N-dimethylaminosulfonyl, aminosulfonyl, N-methylaminosulfonyl, N-ethylsulfonyl, 2,2-dimethylethylaminosulfonyl, N, N-dimethylaminosulfonyl, N- (2-methyl) Propyl) aminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl or phenyl; or wherein R ⁴ is the carbon atom to which it is attached and the ring E Forms a naphthyl radical with the remainder;
90. The composition of claim 89. Said cyclooxygenase-2 selective inhibitor has the following formula:

[Where:
G is oxygen or sulfur;
R ⁸ is trifluoromethyl or pentafluoroethyl;
R ⁹ is chloro or fluoro;
R ¹⁰ is H, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, benzylaminosulfonyl, phenylethylaminosulfonyl, Methylpropylaminosulfonyl, methylsulfonyl, or morpholinosulfonyl;
R ¹¹ is H, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, or phenyl; and R ¹² is H, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, Or phenyl;
90. The composition of claim 89 comprising the compound of: Said cyclooxygenase-2 selective inhibitor has the following formula:

[Where:
A is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclyl ring;
R ₁ is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R ¹ is alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, Optionally substituted at substitutable positions with one or more radicals selected from arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
R ₂ is selected from the group consisting of methyl or amino; and R ₃ is H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cyclo Alkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, Aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocal Nilalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkyl Amino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, Aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, aryl Ruhoniru is selected from the group consisting of radicals chosen from N- alkyl -N- arylaminosulfonyl;]
67. The composition of claim 66 comprising the compound of: Said cyclooxygenase-2 selective inhibitor has the following formula:

68. The composition of claim 66, comprising: Said cyclooxygenase-2 selective inhibitor has the following formula:

68. The composition of claim 66, comprising:   68. The composition of claim 66, wherein the cyclooxygenase-2 selective inhibitor comprises 4- [4- (methyl) -sulfonyl) phenyl] -3-phenyl-2 (5H) -furanone.   68. The composition of claim 66, wherein the cyclooxygenase-2 selective inhibitor comprises 4- (5-methyl-3-phenyl-4-isoxazolyl).   68. The composition of claim 66, wherein the cyclooxygenase-2 selective inhibitor comprises 2- (6-methylpyrid-3-yl) -3- (4-methylsulfonylphenyl) -5-chloropyridine.   68. The composition of claim 66, wherein the cyclooxygenase-2 selective inhibitor comprises 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl]. Stuff.   68. The composition of claim 66, wherein the cyclooxygenase-2 selective inhibitor comprises N-[[4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonyl].   The cyclooxygenase-2 selective inhibitor comprises 4- [5- (3-fluoro-4-methoxyphenyl) -3-difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide. 66. The composition according to 66.   68. The composition of claim 66, wherein the cyclooxygenase-2 selective inhibitor comprises (S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid. Stuff.   The cyclooxygenase-2 selective inhibitor is 2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) 68. The composition of claim 66 comprising pyridazinone. Said cyclooxygenase-2 selective inhibitor has the following formula:

[Where:
R ¹⁶ is methyl or ethyl;
R ¹⁷ is chloro or fluoro;
R ¹⁸ is hydrogen or fluoro;
R ¹⁹ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy;
R ²⁰ is hydrogen or fluoro; and R ²¹ is chloro, fluoro, trifluoromethyl or methyl;
Provided that when R ¹⁶ is ethyl and R ¹⁹ is H, R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are not all fluoro;
67. The composition of claim 66 comprising the compound of:   The composition of claim 1, wherein the cyclooxygenase-2 selective inhibitor is a pharmaceutically acceptable salt or prodrug. R ¹⁶ is ethyl;
R ¹⁷ and R ¹⁹ are chloro;
R ¹⁸ and R ²⁰ are hydrogen; and R ²¹ is methyl;
108. The composition of claim 107. Said cyclooxygenase-2 selective inhibitor has the following formula:

[Where:
X is O or S;
J is a carbocyclic or heterocyclic ring;
R ²² is NHSO ₂ CH ₃ or F;
R ²³ is H, NO ₂ , or F; and R ²⁴ is H, NHSO ₂ CH ₃ , or (SO ₂ CH ₃ ) C ₆ H ₄ ;]
67. The composition of claim 66 comprising the compound of: Said cyclooxygenase-2 selective inhibitor has the following formula:

[Where:
T and M are independently a radical derived from a heterocycle containing phenyl, naphthyl, 5 to 6 members and carrying 1 to 4 heteroatoms, or saturated with 3 to 7 carbon atoms. A radical derived from a hydrocarbon ring;
Q ¹ , Q ² , L ¹ or L ² is independently hydrogen, halogen, lower alkyl having 1 to 6 carbon atoms, trifluoromethyl, or lower methoxy having 1 to 6 carbon atoms; And at least one of Q ¹ , Q ² , L ¹ or L ² is in the para position and is —S (O) _n —R, wherein n is 0, 1, or 2, and R is 1 or to a lower haloalkyl radical or -SO ₂ NH ₂ with a lower alkyl radical or 1 to 6 carbon atoms having 6 carbon atoms; or
Q ¹ and Q ² are methylenedioxy; or L ¹ and L ² are methylenedioxy; and R ²⁵ , R ²⁶ , R ²⁷ , and R ²⁸ are independently hydrogen, halogen, 1 Is a lower alkyl having 6 to 6 carbon atoms, a lower haloalkyl having 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl; or R ²⁵ And R ²⁶ is O; or R ²⁷ and R ²⁸ are O; or R ²⁵ and R ²⁶ together with the carbon atom to which they are attached 3-7 carbon atoms. or form a saturated hydrocarbon ring having; or R ^27, R ²⁸ is a saturated hydrocarbon having to these 3 free together with the carbon atoms connecting 7 carbon atoms To form a ring;]
67. The composition of claim 66 comprising the compound of:   68. The composition of claim 66, wherein the cyclooxygenase-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib, valdecoxib, etoroxib, parecoxib, and deracoxib.   111. The composition of any one of claims 66 or 111, wherein the carbonic anhydrase inhibitor is selected from the group consisting of acetazolamide, metazolamide, diclofenamide, dorzolamide, and brinzolamide.   68. The composition of claim 66, wherein the carbonic anhydrase inhibitor is a geometric isomer, stereoisomer, or tautomer.   114. The composition of claim 113, wherein the carbonic anhydrase inhibitor inhibits carbonic anhydrase activity by about 25% or more at a concentration of about 100 [mu] M or less.   114. The composition of claim 113, wherein the carbonic anhydrase inhibitor inhibits carbonic anhydrase activity by about 50% or more at a concentration of about 100 [mu] M or less.   114. The composition of claim 113, wherein the carbonic anhydrase inhibitor inhibits carbonic anhydrase activity by about 75% or more at a concentration of about 100 [mu] M or less.   68. The composition of claim 66, wherein the cyclooxygenase-2 selective inhibitor is a geometric isomer, stereoisomer, or tautomer.   118. The composition of claim 117, wherein the cyclooxygenase-2 selective inhibitor inhibits cyclooxygenase-2 activity by about 25% or more at a concentration of about 100 [mu] M or less.   118. The composition of claim 117, wherein the cyclooxygenase-2 selective inhibitor inhibits cyclooxygenase-2 activity by about 50% or more at a concentration of about 100 [mu] M or less.   118. The composition of claim 117, wherein the cyclooxygenase-2 selective inhibitor inhibits cyclooxygenase-2 activity by about 75% or more at a concentration of about 100 [mu] M or less.